ascorbic-acid and Arteriosclerosis

The generation by genetic engineering of two murine models to investigate atherosclerosis, such as the apoE- and LDLr- deficient mice, is providing an extraordinaire knowledge of the effect of different nutrients on this complex disease. The present revision provides a comprehensive overview of the advances in this field that point to a remarkable complexity. While some controversies over puzzling results could be explained invoking potential nutrient interactions or different food sources of nutrients, it also appears that other factors such as sex, genetic background or immunological status are emerging as generators of differential responses to nutrients during the atherosclerotic process.

Topics: Alcohol Drinking; Allergy and Immunology; Animals; Antioxidants; Apolipoproteins E; Arginine; Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Cell Proliferation; Dietary Fats; Disease Models, Animal; Energy Metabolism; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Genetic Engineering; Genetic Variation; Genomics; Homocysteine; Insulin Resistance; Iron; Magnesium; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Models, Genetic; Phytosterols; Receptors, LDL; Sex Factors; Sodium; Taurine; Vitamin E

Deregulated crosstalk within nuclear receptor/transcription factor family, comprising of peroxisome proliferator-activated receptors (PPARs) and liver X receptor-alpha (LXR-alpha), can give rise to cooperativity between lipid peroxidation and inflammation leading to atherogenic process. The present study addressed to explore the effect of statins and vitamin 'C' on transcriptional expression of genes coding for this nuclear receptor/transcription factor family within mononuclear cells revealed for the first time that both mevastatin and vitamin 'C' have common action in that they significantly downregulate the expression of PPARs (alpha, gamma) genes and upregulate LXR-alpha gene expression as compared to the control. The similar phenomenon was observed in mononuclear cells obtained from coronary heart disease (CHD) patients who were receiving atorvastatin treatment (20 mg HS). Further, the observed upregulatory effect of LXR-alpha gene expression was in conformity with the downregulatory effect of LXR-alpha on its effector gene matrix metalloproteinase-9. Based on these results, we propose that LXR-alpha-dependent signaling pathway may be a crucial target for the therapeutic intervention in human CHD, and in addition to statins, vitamin 'C' deserves a close scrutiny for the treatment of CHD.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; DNA-Binding Proteins; Free Radical Scavengers; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukocytes, Mononuclear; Lipid Peroxidation; Liver X Receptors; Lovastatin; Molecular Sequence Data; Orphan Nuclear Receptors; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction

This review focuses on the process of arteriosclerosis arising from oxidative stress on lipoproteins and the general failure of randomized human trials using vitamins to retard this process.. As well as clinical trials, the paper reviews the mechanisms by which a variety of oxidants act. Antioxidants are discussed, emphasizing interactions of vitamins C and E with transition metals that can lead to prooxidation. There is a focus on interactions between supplemental or co-antioxidants that counterbalance prooxidant effects of one another.. It is concluded that normal cellular supplementation mechanisms are poorly accessible in the arteriosclerotic plaque leading to a prooxidant environment in which the haphazard introduction of vitamins could potentially be hazardous. Continued investigations into basic and clinical redox interactions of the kind discussed in this review using new measuring techniques may lead to approaches whereby antioxidants can be introduced into tissue in controlled ways for reducing arteriosclerosis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Clinical Trials as Topic; Dietary Supplements; Humans; Vitamin E

Results from experimental and epidemiologic studies suggest an influence of oxidative stress on development and progression of atherosclerosis in man. Prospective endpoint studies failed to support this hypothesis. The current literature is summarized in this review.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Ascorbic Acid; Aspirin; beta Carotene; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Free Radicals; Humans; Male; Nutritional Physiological Phenomena; Oxidative Stress; Placebos; Platelet Aggregation Inhibitors; Primary Prevention; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Tocopherols; Vitamins

Vitamin C (ASC) is well known as an outstanding antioxidant in animal tissues. This concept is reviewed from a chemical standpoint, starting from a chemical view of radical reactions in the cell. ASC, vitamin E, and lipid hydroperoxide were selected as key molecules involved in radical reactions in the cell, and their efficiencies as an index of oxidative stress were evaluated. At first, methods for specific and sensitive determination of ASC and lipid hydroperoxide were developed. Based on comparisons of these indices during oxidative stress in typical pathological conditions, such as diabetes and liver damage by toxicants, ASC concentration was found to be the most sensitive index in animal tissues. Antioxidative effect of food factors in vivo can be evaluated on the basis of these indices. Analysis of oxidation of low-density lipoprotein (LDL) revealed that degradation and cross-link of apolipoprotein B-100 (apoB) are extremely facile processes. Fragmented and conjugated apoB proteins are present in normal human serum, and tend to increase with age based on immunoblot analysis. Estimation of these products allows us a mechanism-based diagnosis of atherosclerosis. A significant relationship between plasma ASC level and the sum of these apoB products was found. In conclusion, specifically determined ASC concentration sensitively reflects oxidative stress in tissues.

Topics: Animals; Apoptosis; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Dehydroascorbic Acid; Food; Humans; In Vitro Techniques; Lipid Peroxides; Mice; Molecular Structure; Organ Specificity; Oxidative Stress; Rats; Reactive Oxygen Species; Vitamin E

Oxidative stress is involved in the pathogenesis of atherosclerosis, while a variety of antioxidants has been used in clinical studies, during the past few years, for the prevention and treatment of atherosclerosis. In small clinical studies it was found that both vitamins C and E may improve endothelial function in patients with risk factors for atherosclerosis such as diabetes mellitus, smoking, hypertension, or hypercholesterolemia. However, the initial, hopeful reports regarding the beneficial role of antioxidant vitamins against atherosclerosis, derived from purely observational studies, were followed by the negative results of almost all large randomized trials. Therefore, treatment with antioxidant vitamins C and E should not be recommended for the prevention or treatment of coronary atherosclerosis. New antioxidant strategies are needed to clarify the exact role of antioxidant treatment in coronary atherosclerosis.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Coronary Artery Disease; Diabetes Complications; Diet; Endothelium, Vascular; Female; Follow-Up Studies; Free Radicals; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Oxidative Stress; Prospective Studies; Randomized Controlled Trials as Topic; Risk; Risk Factors; Smoking; Time Factors; Vitamin E

FREE RADICALS AND THE THEORY OF AGING: Severe oxidative stress progressively leads to cell dysfunction and ultimately cell death. Oxidative stress is defined as an imbalance between pro-oxidants and/or free radicals on the one hand, and anti-oxidizing systems on the other. The oxygen required for living may indirectly be responsible for negative effects; these deleterious effects are due to the production of free radicals, which are toxic for the cells (superoxide anions, hydroxyl radicals, peroxyl radicals, hydrogen peroxide, hydroperoxides and peroxinitrite anions). Free radical attacks are responsible for cell damage and the targeted cells are represented by the cell membranes, which are particularly rich in unsaturated fatty acids, sensitive to oxidation reactions; DNA is also the target of severe attacks by these reactive oxygen species (ROS).. These are represented by the enzymes and free radical captors. The latter are readily oxidizable composites. The free radical captor or neutralization systems of these ROS use a collection of mechanisms, vitamins (E and C), enzymes [superoxide dismutase (SOD), glutathion peroxidase (GPx) and others], and glutathion reductase (GSH), capable of neutralizing peroxinitrite. The efficacy of this system is dependent on the genome for the enzymatic defence systems, and on nutrition for the vitamins. Some strategies aimed at reducing oxidative stress-related alterations have been performed in animals. However, only a few can be used and are efficient in humans, such as avoidance of unfavourable environmental conditions (radiation, dietary carcinogens, smoking...) and antioxidant dietary supplementation.. Epidemiological data suggest that antioxidants may have a beneficial effect on many age-related diseases: atherosclerosis, cancer, some neurodegenerative and ocular diseases. However, the widespread use of supplements is hampered by several factors: the lack of prospective and controlled studies; insufficient knowledge on the pro-oxidant, oxidant and ant-oxidant properties of the various supplements; growing evidence that free radicals are not only by-products, but also play an important role in cell signal transduction, apoptosis and infection control.. Although current data indicate that antioxidants cannot prolong maximal life span, the beneficial impact of antioxidants on various age-related degenerative diseases may forecast an improvement in life span and enhance quality of life. The current lack of sufficient data does not permit the systematic recommendation of anti-oxidants. Nevertheless, antioxidant-rich diets with fruit and vegetables should be recommended.

Topics: Aging; Alzheimer Disease; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotenoids; Cataract; Chronic Disease; Disease Models, Animal; Evidence-Based Medicine; Free Radicals; Humans; Lutein; Macular Degeneration; Neoplasms; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Vitamin E

The development of arteriosclerosis is the limiting factor for the long-term survival and the major cause of mortality in patients with heart transplants. Various factors, including oxidative stress, contribute to the progression of the disease. In a recent clinical trial using the intravascular ultrasound technique, which detects the early stages of disease development, supplementation with vitamins C and E retarded the progression of coronary arteriosclerosis during the early stage following cardiac transplantation.

Topics: Arteriosclerosis; Ascorbic Acid; Dietary Supplements; Endothelium, Vascular; Heart Transplantation; Humans; Oxidative Stress; Vitamin E

A plethora of agents have been proposed to combat atherosclerosis, and many of these come from outside mainstream medicine. The majority have anti-oxidant properties, which is the scientific basis for their supposed action. Some of these agents have been evaluated carefully in randomized, double-blinded studies, whereas others have gained popularity despite a paucity of valid data. Although many are prescribed or physician recommended, most are used without the knowledge of the patient's physician. In some cases these "medications" may have harmful side effects or impact negatively on other aspects of the patients medical or surgical care. Others, however, may be extremely beneficial although not utilized because the doctor is unaware of their potential. Accordingly, it is important that the vascular surgeon become acquainted with these compounds. This report attempts to summarize the most commonly used herbs, vitamins, foods and other sundry "treatments" and makes recommendations for their use based on our current understanding of their scientific and clinical merit.

Topics: Alcohol Drinking; Antioxidants; Arginine; Arteriosclerosis; Ascorbic Acid; Cholesterol, LDL; Complementary Therapies; Diet; Estrogen Replacement Therapy; Ginkgo biloba; Humans; Hyperhomocysteinemia; Particle Size; Vitamin E

Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. ASAP was a 6-year randomized trial to study the effect of supplementation with vitamin E plus slow-release vitamin C on carotid atherosclerotic progression in 520 hypercholesterolemic men and women aged 45-69 years. The supplementation reduced the progression of carotid atherosclerosis by 26% (P = 0.014), by 33% (P = 0.024) in men and 14% (not significant) in women. The effect was larger in subjects with low baseline vitamin C or atherosclerotic plaques. In the Harvard IVUS trial, the combined supplementation with vitamins E and C significantly inhibited the progression of coronary atherosclerosis in one year. These data confirm that the supplementation with a combination of vitamins E and C can retard atherosclerotic progression. The findings of completed trials testing the effect on cardiovascular events are less consistent. The major on-going clinical trials include the SU.VI.MAX, WHS, WACS and WAVE studies. These involve in total over 80,000 subjects, who are treated with antioxidative supplements for years. The results of these studies will become available during 2003-2006. They may provide the necessary additional information concerning the effect of antioxidants on cardiovascular events.

Topics: Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular System; Clinical Trials as Topic; Disease Progression; Female; Humans; Male; Middle Aged; Time Factors; Vitamin E

People who consume a diet rich in fruit and vegetables have lower risks of cancer, cardiovascular disease and all-cause mortality. Many prospective cohort studies have reported inverse associations between dietary intake or blood levels of beta-carotene and risks of cancer. Several large-scale trials were set up to assess whether beta-carotene supplementation might reduce the risk of cancer. Subsequently, evidence emerged from basic research which indicated that oxidative modification of low-density lipoprotein cholesterol increases its atherogenicity. The evidence from basic research, and epidemiological evidence for a possible protective effect of antioxidant vitamins for cardiovascular disease was strongest for vitamin E. More recently, further trials were set up to examine if supplementation with anti-oxidant vitamins might also reduce the risk of cardiovascular disease. This review summarises the available randomised evidence from published trials of beta-carotene supplementation involving 70,000 people from 3 large-scale trials in healthy populations and on vitamin E supplementation involving 29,000 patients at high-risk of cardiovascular disease from 5 large-scale trials. The results of these trials have been disappointing and failed to confirm any protective effect of these vitamins for either cancer or for cardiovascular disease.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Cardiovascular Diseases; Carotenoids; Cholesterol, LDL; Humans; Lycopene; Oxidative Stress; Randomized Controlled Trials as Topic; Risk Assessment; Vitamin E; Vitamins

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Biomarkers; DNA Damage; Humans; Lipid Metabolism; Lipid Peroxidation; Neoplasms; Nutritional Requirements; Oxidation-Reduction; Oxidative Stress; Proteins; Reactive Oxygen Species; Smoking; Vitamin E

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotenoids; Clinical Trials as Topic; Coronary Disease; Fatty Acids, Monounsaturated; Flavonoids; Fluvastatin; Humans; Indoles; Oxidative Stress; Phenols; Polymers; Polyphenols; Probucol; Vitamin E

Dehydroascorbic acid, the oxidized form of vitamin C, is transported into mammalian cells via facilitative glucose transporters and hyperglycemia inhibits this process by competitive inhibition. This inhibited transport may promote oxidative stress and contribute to the increase in atherosclerotic cardiovascular disease observed in patients with diabetes mellitus. This review explores the importance of this proposed mechanism in light of current research. For example, recent reports suggest that administration of antioxidants, such as vitamin C, may slow atherogenesis by improving endothelium-dependent vasodilation in individuals with abnormal glucose and lipid metabolism, perhaps by preventing the oxidation of nitric oxide, an important regulator of vasomotor tone. Endothelial dysfunction plays a key role in the development of atherosclerosis and endothelial cells may be particularly affected by hyperglycemia-induced ascorbic acid deficiency as they line the interior of blood vessels. In addition, we discuss evidence of several other mechanisms by which vitamin C status may affect the development of atherosclerotic cardiovascular disease, particularly its inverse relationship to multiple cardiovascular disease risk factors and indicators. Given these factors, vitamin C administration is recommended during periods of both acute and chronic hyperglycemia to help preserve endothelial function.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Collagen; Endothelium, Vascular; Humans; Hyperglycemia

Oxidation is a biochemical process of loss of electrons associated with another of reception called reduction. This process is capital for life, because it takes part in the production of cellular energy. Oxidative stress appears when oxidation is excessive. This reality is complex in all biological levels, and cannot be measured or defined by a single parameter. A great number of diseases have been related to oxidative stress and generation of free radicals. For this reason, antioxidant therapies and diets (such as mediterranean diet) rich or enriched with antioxidants seem to prevent or at least to attenuate the organic deterioration originated by an excessive oxidative stress.

Topics: Acute Kidney Injury; Aged; Aging; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Cataract; Diabetes Mellitus; Diet; Humans; Hypertension; Liver Diseases; Neoplasms; Oxidation-Reduction; Oxidative Stress; Primary Prevention; Risk Factors; Selenium; Vitamin E

Human coronary and peripheral arteries show endothelial dysfunction in a variety of conditions, including atherosclerosis, hypercholesterolemia, smoking, and hypertension. This dysfunction manifests as a loss of endothelium-dependent vasodilation to acetylcholine infusion or sheer stress, and is typically associated with decreased generation of nitric oxide (NO) by the endothelium. Vitamin C, or ascorbic acid, when acutely infused or chronically ingested, improves the defective endothelium-dependent vasodilation present in these clinical conditions. The mechanism of the ascorbic acid effect is unknown, although it has been attributed to an antioxidant function of the vitamin to enhance the synthesis or prevent the breakdown of NO. In this review, multiple mechanisms are considered that might account for the ability of ascorbate to preserve NO. These include ascorbate-induced decreases in low-density lipoprotein (LDL) oxidation, scavenging of intracellular superoxide, release of NO from circulating or tissue S-nitrosothiols, direct reduction of nitrite to NO, and activation of either endothelial NO synthase or smooth muscle guanylate cyclase. The ability of ascorbic acid supplements to enhance defective endothelial function in human diseases provides a rationale for use of such supplements in these conditions. However, it is first necessary to determine which of the many plausible mechanisms account for the effect, and to ensure that undesirable toxic effects are not present.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Coronary Vessels; Endothelium, Vascular; Enzyme Activation; Guanylate Cyclase; Humans; Lipoproteins, LDL; Mercaptoethanol; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Nitroso Compounds; Oxidation-Reduction; Oxidative Stress; Rabbits; S-Nitrosothiols; Sulfhydryl Compounds; Superoxides; Vasodilation

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Dietary Supplements; Endothelium, Vascular; Flavonoids; Humans; Lipid Peroxidation; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Vitamin E

The premise that oxidative stress, among several other factors, plays an important role in atherogenesis implies that the development and progression of atherosclerosis can be inhibited by antioxidants. In this minireview we discuss several mechanisms by which the antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) may protect against atherosclerosis. These mechanisms include inhibition of LDL oxidation and inhibition of leukocyte adhesion to the endothelium and vascular endothelial dysfunction. Overall, ascorbate appears to be more effective than alpha-tocopherol in mitigating these pathophysiological processes, most likely as a result of its abilities to effectively scavenge a wide range of reactive oxygen and nitrogen species and to regenerate alpha-tocopherol, and possibly tetrahydrobiopterin, from its radical species. In contrast, alpha-tocopherol can act either as an antioxidant or a pro-oxidant to inhibit or facilitate, respectively, lipid peroxidation in LDL. However, this pro-oxidant activity of alpha-tocopherol is prevented by ascorbate acting as a coantioxidant. Therefore, an optimum vitamin C intake or body status may help protect against atherosclerosis and its clinical sequelae, whereas vitamin E may only be effective in combination with vitamin C.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cell Adhesion; Cells, Cultured; Disease Models, Animal; E-Selectin; Endothelium, Vascular; Enzyme Activation; Humans; Leukocytes; Lipid Peroxidation; Lipoproteins, LDL; Nitric Oxide; Oxidation-Reduction; Protein Kinase C; Reactive Oxygen Species; Vasodilation; Vitamin E

The faith that an oxidizing of LDL is necessary for he foam cell formation is basically for the so called oxidative hypothesis of atherosclerosis. The role of LDL-oxidation for the atherosclerotic plaque formation, as well as its association with inflammatory processes in the vascular wall, are well established. The important conclusion of this hypothesis is the possible role of the antioxidants attenuating atherosclerotic mechanisms. The advances in studying the principal antioxidant vitamins E, C and beta-carotene effects, revealed a great part of their molecular mechanisms, which are not necessarily antioxidative. The important aspects of the cooperative antioxidant action are revealed too, including the so called tocopherol-mediated peroxidation, suggesting the need for the co-antioxidants for effective antioxidant defense. In the recent years many vitamin antioxidant supplementations are used. The epidemiological results of such supplementation do not always reveal the same beneficial effects as expected theoretically or based on the observations made with a diet rich in fruits and vegetables. The present paper generalizes the thought concerning the impact of oxidized LDL in atherosclerosis, as well as mechanisms of action and pharmacokinetiks of the most widely used antioxidant vitamins--E, C and beta-carotene, and the perspectives of their usage in cardiovascular prophylaxy bazed upon the recent experience in antioxidant vitamin supplementation.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Cardiovascular Diseases; Dietary Supplements; Humans; Lipoproteins, LDL; Oxidative Stress; Vitamin E

Elevated levels of lipid peroxidation and increased formation of reactive oxygen species within the vascular wall in atherosclerosis can overwhelm cellular antioxidant defence mechanisms. Accumulating evidence implicates oxidatively modified low density lipoproteins (LDL) in vascular dysfunction in atherosclerosis and oxidized LDL have been localized with in atherosclerotic lesions. We here report that human oxidatively modified LDL induce expression of 'antioxidant-like' stress proteins in vascular cells, involving increases in the activity of L-cystine transport, glutathione synthesis, heme oxygenase-1 and the murine stress protein MSP23. Moreover, treatment of human arterial smooth muscle cells with the dietary antioxidant vitamin C markedly attenuates adaptive increases in endogenous antioxidant gene expression and affords protection against smooth muscle cell apoptosis induced by moderately oxidized LDL. As vascular cell death is a key feature of atherosclerotic lesions and may contribute to the plaque 'necrotic' core, cap rupture and thrombosis, our findings suggest that the cytoprotective actions of vitamin C could limit plaque instability in advanced atherosclerosis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Endothelium, Vascular; Free Radicals; Humans; Lipid Peroxidation; Muscle, Smooth, Vascular; Reactive Oxygen Species

The importance of specific determination of key molecules involved in radical reaction is discussed in the evaluation of oxidative stress in animal tissues. As an effective index of oxidative stress, the concentration of lipid hydroperoxides, which is determined by a specific and sensitive method developed by the authors, is discussed firstly. The efficiency of the indicator is demonstrated by several results that it increases in tissues of aged, vitamin C-deficient, vitamin E-deficient, iron-overloaded, or streptozotocin-induced diabetic rats. The other indicator, tissue vitamin C, which is also determined by a specific and sensitive method developed by the authors, is discussed. Based on the method, the profile of vitamin C decrease in tissues of ODS rats, which cannot synthesize the vitamin inherently, was determined and the in vivo interaction between vitamin C and vitamin E was demonstrated for the first time. The roles of oxidative stress in diabetes mellitus, atherosclerosis, and cell death (necrosis and apoptosis) were also discussed.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Diabetes Mellitus, Experimental; Humans; Lipid Peroxides; Lipoproteins, LDL; Oxidative Stress; Rats; Vitamin E

Oxidative stress has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction. Antioxidants may inhibit atherogenesis and improve vascular function by two different mechanisms. First, lipid-soluble antioxidants present in low-density lipoprotein (LDL), including alpha-tocopherol, and water-soluble antioxidants present in the extracellular fluid of the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation through an LDL-specific antioxidant action. Second, antioxidants present in the cells of the vascular wall decrease cellular production and release of reactive oxygen species (ROS), inhibit endothelial activation (i.e., expression of adhesion molecules and monocyte chemoattractants), and improve the biologic activity of endothelium-derived nitric oxide (EDNO) through a cell- or tissue-specific antioxidant action. alpha-Tocopherol and a number of thiol antioxidants have been shown to decrease adhesion molecule expression and monocyte-endothelial interactions. Vitamin C has been demonstrated to potentiate EDNO activity and normalize vascular function in patients with coronary artery disease and associated risk factors, including hypercholesterolemia, hyperhomocysteinemia, hypertension, diabetes, and smoking.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Chemokine CCL2; Humans; Lipoproteins, LDL; Nitric Oxide; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vitamin E

Topics: Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Humans; Primary Prevention; Prospective Studies; Vitamin A; Vitamin E

There is substantial evidence for a role of dietary antioxidants in the prevention of cardiovascular disease, but evidence for a protective effect of vitamin C is inconclusive. Two recent reports add to the supporting evidence and provide some new observations. The first study, a 5-year prospective population study of Finnish men, suggests that vitamin C-deficient men may be at increased risk of myocardial infarction. The second study suggests that vitamin C may play a role in preventing manifestations of existing coronary artery disease, rather than in limiting disease progression. Although these results suffer from the limitations of observational studies, they provide impetus for further investigation.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Female; Humans; Male; Nutritional Physiological Phenomena; Prospective Studies; Risk Factors

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Depression, Chemical; Humans; In Vitro Techniques; Lipid Peroxides; Male; Oxidative Stress; Rabbits; Rats; Vitamin E

The notion that oxidation of lipids and lipoproteins may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. It is hypothesized that dietary antioxidants may help prevent development and progression of atherosclerosis. The available evidence helps substantiate this hypothesis but is not yet conclusive. The results of several ongoing large randomized intervention trials will provide valuable information about the efficacy and safety of supplemental dietary antioxidants in prevention of atherosclerosis.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotenoids; Clinical Trials as Topic; Flavonoids; Humans; Selenium; Vitamin E

Increased production of reactive oxygen species is a feature of most, if not all, human disease, including cardiovascular disease and cancer. Dietary antioxidants may be especially important in protecting against human diseases associated with free radical damage to cellular DNA, lipids, and proteins. Ascorbic acid is an effective water-soluble antioxidant, and epidemiologic studies suggest that increased ascorbate nutriture is associated with reduced risk of some degenerative diseases, especially cancer and eye cataracts. Population studies have also shown that high vitamin E intakes are associated with decreased risk of coronary heart disease, possibly as a result of inhibition of atherogenic forms of oxidized low-density lipoprotein. Recent data suggest that beta-carotene provides protection against lipid peroxidation in humans, as well as provitamin A activity. Yet, present data are not sufficient to quantitate micronutrient requirements needed to protect against oxidative damage. The antioxidant roles of many food constituents, such as polyphenols, have not been clarified. Most antioxidants can act as prooxidants under certain conditions, and more research is needed to determine the occurrence and importance of this in vivo. The few controlled intervention trials carried out so far have shown mixed results as to the potential of antioxidant supplements for reducing the incidence of chronic diseases. Definitive recommendations on antioxidant intakes for disease prevention must await evidence from controlled studies and intervention trials, some currently in progress. Overall, the present data suggest that protection against oxidative damage and related disease is best served by the variety of antioxidant substances found in fruit and vegetables.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Carotenoids; Exercise; Homocysteine; Humans; Lipid Peroxidation; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Vitamin E

In this chapter, we have briefly reviewed the current scientific knowledge of the role of vitamin C in the prevention of atherosclerosis and its associated clinical manifestations. There is good evidence from animal studies that vitamin C can slow the progression of experimental atherosclerosis. Most of these studies, however, were done either in guinea pigs, using ascorbic acid depletion, or in cholesterol-fed rabbits, using ascorbic acid supplementation. Both animal models have limitations, as guinea pigs are not a well-established (nor well-studied) model of atherosclerosis, and rabbits develop atherosclerosis at high serum beta-VLDL cholesterol levels, and in addition can synthesize ascorbic acid. In contrast, humans develop atherosclerosis spontaneously and readily at moderately elevated serum LDL cholesterol levels and have lost the ability to synthesize ascorbic acid. Thus, the animal studies discussed, although quite promising and suggestive of an anti-atherogenic effect of ascorbic acid, need to be expanded to primates before more definitive conclusions can be drawn. Similar to the animal data, the current evidence from epidemiological studies on the role of vitamin C in the prevention of CVD is inconclusive, with some studies showing a very strong correlation between increased vitamin C intake and incidence of CVD events and other studies showing no correlation at all. Studies on CVD risk factors indicate that vitamin C may moderately decrease total serum cholesterol levels, increase HDL levels, and exert a hypotensive effect. These findings are particularly intriguing and should be pursued vigorously in basic research studies to elucidate biological mechanisms. In addition, it appears that large placebo-controlled, double-blind, randomized trials of vitamin C supplementation (without simultaneous supplementation with vitamin E) in populations with a wide range of vitamin C body levels are needed in order to confirm or refute a role for vitamin C in the prevention of CVD. Unfortunately, no such trials are currently being conducted. The possible mechanisms by which ascorbic acid may affect the development of atherosclerosis and the onset of acute coronary events include effects on arterial wall integrity related to biosynthesis of collagen and GAGs, altered cholesterol metabolism mediated by vitamin C-dependent conversion of cholesterol to bile acids, and effects on triglyceride levels via modulation of lipoprotein lipase activity. A particularly

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Cholesterol; Diet, Atherogenic; Disease Models, Animal; Epidemiologic Methods; Extracellular Matrix Proteins; Guinea Pigs; Humans; Lipoproteins; Rabbits; Risk Factors

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Humans; Lipid Peroxidation; Lipoproteins, LDL; Vitamin E

Evidence is increasing that oxidation of low-density lipoprotein cholesterol may be instrumental in atherogenesis. As a result, a number of studies have been undertaken to evaluate the effects of antioxidant vitamins, beta carotene, selenium, and monounsaturated fat on coronary artery disease. Results in many instances have been promising, particularly in the case of vitamin E supplements. Studies of pro-oxidants, such as iron and copper, are inconclusive at this time, and a trial to assess the value of probucol in hypercholesterolemic patients is currently under way.

Topics: Adult; Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Carotenoids; Cholesterol, LDL; Coronary Disease; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Vitamin E

To review the effects of vitamin C (ascorbic acid) on plasma lipid concentrations, and to address the proposed mechanisms through which vitamin C may potentially alter lipid concentrations.. A MEDLINE search was performed to identify pertinent English-language literature including studies, abstracts, and review articles. Key search terms were vitamin C, ascorbic acid, lipoproteins, lipids, and atherosclerosis.. Studies examining the relationships between vitamin C and plasma lipid concentrations including animal, observational, and clinical trials were selected. Because there were no large randomized, controlled clinical trials, data were extracted from all clinical trials, regardless of design. Review articles discussing the effects of vitamin C on plasma lipid concentrations and the atherosclerotic process also were included. Pertinent information, as judged by the authors, was extracted for discussion.. Evidence suggests an inverse relationship between vitamin C intake and the development of atherosclerosis, although the effect has not yet been proven in clinical trials. It has been postulated that this effect might be mediated not only through the antioxidant properties of vitamin C, but also through a plasma lipid-modifying effect. Data from animal and observational trials suggest that high vitamin C concentrations may correlate negatively with concentrations of total cholesterol, triglycerides, and low-density lipoproteins and positively with high-density lipoproteins. Other studies, however, have not confirmed these findings. Similarly, results from clinical trials have been widely variable and inconclusive.. Analysis of the literature suggests an association between vitamin C and plasma lipid concentrations and a potential role in slowing the development of atherosclerosis. Significant variations and inadequacies in trial design, however, prohibit definitive conclusions. On the basis of these preliminary data, it appears that there is justification for additional well-designed trials to further evaluate the relationship between vitamin C and plasma lipid concentrations.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Clinical Trials as Topic; Cross-Sectional Studies; Drug Evaluation, Preclinical; Female; Humans; Lipids; Longitudinal Studies; Male

Despite a realisation that antioxidants will not delay ageing in healthy older people, there is increasing scientific interest in the role of free radical oxidants in a number of diseases associated with older age. For most of these diseases there is suggestive theoretical and laboratory evidence but not confirmatory clinical evidence. Free radical damage seems likely to be significant in the pathophysiology of atherosclerosis, ischaemia-reperfusion injury, Parkinson's disease, cataract, some cancers and rheumatoid arthritis. Evidence to suggest a protective effect from antioxidant vitamins exists for ischaemic heart disease, cataract and some cancers. Attempts to influence the outcome of other diseases such as ischaemia-reperfusion injury, Parkinson's disease and rheumatoid arthritis have so far failed to achieve positive results. Research interest in the field is increasing although hampered by methodological difficulties and the limited financial return for drug companies. In the meantime there seems no reason to discourage older people who wish to ingest extra vitamin E and vitamin C. A diet with adequate vegetables and fruits should provide sufficient beta carotene.

Topics: Aged; Aging; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cataract; Diet; Free Radicals; Humans; Parkinson Disease; Reactive Oxygen Species; Reperfusion Injury; Vitamin A; Vitamin E

Recent research findings have suggested a role for pharmacologic as well as nutritional antioxidants in the prevention of atherosclerosis. Data from animal studies as well as cell culture experiments have shown that the drug probucol, which has hypocholesterolemic and antioxidant properties, is able to prevent oxidative modification of low density lipoproteins (LDL). Such modification is now believed to play a major part in the initiation and progression of arterial lesions. Nutrients with antioxidant properties such as vitamins C and E, beta-carotene, and mono-unsaturated fatty acids (when they replace polyunsaturated fatty acids) can reduce the susceptibility of LDL to oxidation. Antioxidant therapy, if proven useful, should be considered an adjunct to lipid-lowering therapy in order to have the greatest impact on coronary heart disease.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotenoids; Disease Models, Animal; Fatty Acids, Monounsaturated; Humans; Lipoproteins, LDL; Oxidation-Reduction; Rabbits; Vitamin E

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Humans; Lipoproteins, LDL; Oxidation-Reduction; Probucol; Thiobarbituric Acid Reactive Substances; Vitamins

The very extensive research into atherogenesis carried out in recent years has yielded new knowledge of the importance of oxidation by free radicals of low-density lipoproteins and lipids, for instance in endothelial cell membrane. This has provided greater insight into the potential benefit of preventive measures using anti-oxidants to inhibit atherogenesis, and the results of clinical trials carried out so far would seem to confirm this. Prospective, controlled epidemiological trials are still lacking, but this will probably be remedied within the next 2-3 decades. The most clinically interesting antioxidants are vitamins C and E, beta-carotene, the ubiquinones, and the trace element selenium, substances that are naturally integrated components of the complex biochemistry of the human organism. The review is intended to clarify the scientific rationale for an increased intake of such anti-oxidants with a view to reducing the incidence of ischaemic vascular disorders.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Carotenoids; Clinical Trials as Topic; Free Radicals; Humans; Ubiquinone; Vitamin E

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Carotenoids; Cholesterol; Chromatography, High Pressure Liquid; Diet; Energy Intake; Epidemiologic Methods; Fatty Acids, Unsaturated; Free Radicals; Humans; Lipid Peroxides; Lipoproteins; Models, Biological; Risk; Selenium; Vitamin A; Vitamin E

Topics: Aged; Animals; Arteriosclerosis; Ascorbic Acid; Avitaminosis; Calcium; Humans; Lipid Metabolism; Thrombosis; Vitamin A; Vitamin B Complex; Vitamin E; Vitamin K; Vitamins

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cells, Cultured; Chloroquine; Fibroblasts; Humans; In Vitro Techniques; Lipoproteins, HDL; Lipoproteins, LDL; Lysosomes; Models, Biological; Muscle, Smooth; Phosphatidylcholine-Sterol O-Acyltransferase; Rats; Sterol Esterase

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholelithiasis; Cholesterol; Diet; Disease Models, Animal; Guinea Pigs; Humans; Lipids; Liver; Rats; Triglycerides

Topics: Adolescent; Adult; Anemia, Hypochromic; Arteriosclerosis; Ascorbic Acid; Child; Diet; Female; Humans; Iron; Male; Nutrition Disorders; Nutritional Physiological Phenomena; Obesity; Physical Exertion; Vitamins; Zinc

Topics: Acute Disease; Animals; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Bile Acids and Salts; Cholesterol; Cholesterol, Dietary; Chronic Disease; Fatty Liver; Humans; Hypercholesterolemia; Lipid Metabolism; Liver Cirrhosis; Scurvy

Topics: Acyltransferases; Adult; Animals; Arteries; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholesterol; Disease Models, Animal; Evaluation Studies as Topic; Forecasting; Humans; Phosphatidylcholines; Self Medication

Topics: Aging; Animals; Arteriosclerosis; Ascorbic Acid; Chondroitin; Connective Tissue; Coronary Disease; Diet, Atherogenic; Glycoproteins; Glycosaminoglycans; Heparin; Heparitin Sulfate; Hexosamines; Hexoses; Histamine; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Lipid Metabolism; Lipoproteins, LDL; Mucoproteins; Neuraminic Acids; Rabbits; Rats

Topics: Adult; Aged; Animals; Arteriosclerosis; Ascorbic Acid; Catecholamines; Diet Therapy; Dietary Fats; Fats, Unsaturated; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertension; Injections, Intra-Arterial; Intermittent Claudication; Male; Mice; Middle Aged; Myocardial Infarction; Nicotine; Obesity; Procaine; Rabbits; Radiography; Smoking; Sympathectomy; Thiamine; Thromboangiitis Obliterans; Tolazoline; Vasodilator Agents

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholesterol; Guinea Pigs; Humans; Rabbits

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cholesterol; Glycerides; Humans; Lipase; Lipids; Lipoprotein Lipase; Male; Rabbits; Rats; Triglycerides

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Humans; Metabolism

Topics: Antimetabolites; Arteriosclerosis; Ascorbic Acid; Cholesterol; Choline; Corrinoids; Ethyl Biscoumacetate; Heparin; Humans; Hypercholesterolemia; Iodoacetates; Lipotropic Agents; Magnesium Sulfate; Neomycin; Niacin; Nicotinic Acids; Progesterone; Pyridoxine; Thyroxine; Triparanol; Vitamin B 12

C-reactive protein (CRP) may directly affect the progression of atherosclerosis, and therefore, may be a target for reducing disease risk. The objective was to determine whether antioxidant supplementation reduces plasma CRP in active and passive smokers.. Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to study supplements.. Berkeley and Oakland, California.. Healthy adult men and women, consuming <4 daily servings of fruits and vegetables, and who were actively or passively exposed to cigarette smoke. Analysis was limited to participants with detectable baseline CRP concentrations and no evidence of inflammation associated with acute illness at baseline or follow-up as reflected in CRP elevations (> or =10.0 mg/L). A total of 1393 individuals were screened, 216 randomized, 203 completed the study, and 160 were included in the analysis.. Participants were randomized to receive a placebo or vitamin C (515 mg/day) or antioxidant mixture (per day: 515 mg vitamin C, 371 mg alpha-tocopherol, 171 mg gamma-tocopherol, 252 mg mixed tocotrienols, and 95 mg alpha-lipoic acid).. Change in plasma CRP concentration.. Vitamin C supplementation yielded a 24.0% reduction (95% confidence interval, -38.9% to -5.5%, p = 0.036 compared to control) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction (-23.9% to 19.3%) and 4.3% increase (-15.1% to 28.2%), respectively. Results were adjusted for baseline body mass index and CRP concentrations.. Plasma CRP itself may serve as a potential target for reducing the risk of atherosclerosis, and antioxidants, including vitamin C, should be investigated further to confirm their CRP-lowering and anti-inflammatory effects.

Topics: alpha-Tocopherol; Antioxidants; Arteriosclerosis; Ascorbic Acid; Body Mass Index; C-Reactive Protein; Dietary Supplements; Double-Blind Method; Female; gamma-Tocopherol; Humans; Male; Middle Aged; Placebos; Smoking; Thioctic Acid; Tobacco Smoke Pollution; Tocotrienols; Vitamins

Combination of the antioxidants ascorbic acid in slow release formulation and alpha-tocopherol can retard the progression of atherosclerosis. In order to determine if differences in formulation could explain some of the different results in the intervention trials we determined selected pharmacokinetics for two different formulations of ascorbic acid together with alpha-tocopherol.. Single-blinded, randomised, placebo-controlled intervention study with 48 healthy men, aged 20-65 years, smoking > or = 5 cigarettes/day. Subjects received 250 mg plain release ascorbic acid and 91 mg plain release d-alpha-tocopheryl acetate, 250 mg slow release ascorbic acid and 91 mg plain release d-alpha-tocopheryl acetate or placebo twice daily for 4 weeks. A series of blood samples were collected after administration of the first dose and repeated after 4 weeks of supplementation.. The fluctuation of ascorbic acid plasma concentrations decreased significantly (P = 0.003) after 4 weeks supplementation in the slow versus the plain release group.. This study shows that there were pharmacokinetic differences between plain and slow release formulations of ascorbic acid. However, these effects are small and unlikely to be of significant clinical importance.

Topics: Adult; Aged; alpha-Tocopherol; Antioxidants; Area Under Curve; Arteriosclerosis; Ascorbic Acid; Delayed-Action Preparations; Disease Progression; Humans; Intestinal Absorption; Male; Middle Aged; Single-Blind Method; Smoking

Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT).. The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol > or =5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P=0.014), in men by 33% (95% CI, 4 to 62, P=0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P=0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P=0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol.. These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.

Topics: Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotid Artery Diseases; Carotid Artery, Common; Cholesterol, HDL; Delayed-Action Preparations; Dietary Supplements; Disease Progression; Drug Therapy, Combination; F2-Isoprostanes; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Patient Compliance; Time Factors; Ultrasonography; Vitamin E

At 60 patients with coronary artery disease and high blood pressure studied effects of a diet with low lipid and flavons. The application of a diet and flavons promoted positive dynamics (changes) of clinical manifestations of disease, lipid spectrum and antioxidants.

Topics: Adult; Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Diet; Electrocardiography; Flavonoids; Humans; Hypertension; Lipid Peroxidation; Malondialdehyde; Middle Aged; Myocardial Ischemia; Obesity

Hyperhomocystinemia is a risk factor for cardiovascular disease, and acute elevation of plasma homocysteine after methionine loading impairs endothelial function in healthy subjects. Interestingly, pretreatment with vitamin C can ameliorate this effect. We have already shown that acute oral vitamin C administration reduces arterial stiffness in healthy subjects, and the aim of the present study was to investigate the effect of methionine loading on arterial stiffness with and without concomitant vitamin C using the noninvasive technique of pulse wave analysis. Eight healthy male subjects (mean age, 29 years; range, 20-42 years) were studied on three occasions at weekly intervals. In a double-blind, double-dummy, randomized order they received orally either 100 mg/kg methionine, 100 mg/kg methionine plus 2 g of vitamin C, or matching placebos. Peripheral and central blood pressure, heart rate, cardiac index, arterial stiffness, and plasma homocysteine levels were assessed at baseline and 6 hours after dosing. Compared with placebo, there was no significant change in any of the hemodynamic parameters, including arterial stiffness, after oral methionine, although plasma homocysteine did increase from 11.5 +/- 1.6 to 28.7 +/- 4.4 microM (mean +/- SEM; p < 0.001). Combined methionine and vitamin C led to a similar increase in plasma homocysteine but significantly reduced augmentation index by 10.5 +/- 3.2% (p = 0.02). Acute hyperhomocystinemia does not significantly alter arterial stiffness, as assessed by pulse wave analysis, whereas a combination of methionine and vitamin C leads to a similar reduction in augmentation index to that previously described after vitamin C alone. These data reinforce evidence that vitamin C reduces arterial stiffness but do not indicate any important interaction with oral methionine.

Topics: Adult; Analysis of Variance; Antioxidants; Arteriosclerosis; Ascorbic Acid; Blood Pressure; Double-Blind Method; Drug Combinations; Heart Rate; Hemodynamics; Homocysteine; Humans; Male; Methionine; Vascular Resistance

To study the efficacy of vitamin E and C supplementation on the progression of carotid atherosclerosis, hypothesizing an enhanced preventive effect in men and in smokers and synergism between vitamins.. Double-masked two-by-two factorial trial, randomization in four strata (by gender and smoking status) to receive twice daily either 91 mg (136 IU) of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these or placebo for three years. A randomized sample of 520 smoking and nonsmoking men and postmenopausal women aged 45-69 years with serum cholesterol >/= 5.0 mmol L-1 were studied.. The population of the city of Kuopio in Eastern Finland.. Twice daily either a special formulation of 91 mg of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these (CellaVie(R)) or placebo for three years.. Atherosclerotic progression, defined as the linear regression slope of ultrasonographically assessed common carotid artery mean intima-media thickness (IMT), was calculated over semi-annual assessments.. The average increase of the mean IMT was 0.020 mm year-1 amongst men randomized to placebo and 0.018 mm year-1 in vitamin E, 0.017 mm year-1 in vitamin C and 0.011 mm year-1 in the vitamin combination group (P = 0.008 for E + C vs. placebo). The respective means in women were 0.016, 0.015, 0.017 and 0.016 mm year-1. The proportion of men with progression was reduced by 74% (95% CI 36-89%, P = 0.003) by supplementation with the formulation containing both vitamins, as compared with placebo.. Our study shows that a combined supplementation with reasonable doses of both vitamin E and slow-release vitamin C can retard the progression of common carotid atherosclerosis in men. This may imply benefits with regard to other atherosclerosis-based events.

Topics: Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotid Artery Diseases; Disease Progression; Double-Blind Method; Drug Synergism; Female; Follow-Up Studies; Humans; Male; Middle Aged; Patient Compliance; Smoking; Vitamin E

An elevated plasma total homocysteine level (tHcy) is considered an independent risk factor for atherosclerosis. The mechanisms by which hyperhomocysteinemia induces atherosclerosis are only partially understood, but promotion of LDL oxidation and endothelial injury have been suggested. The purpose of this study was to test the hypothesis that a high plasma tHcy is associated in men with increased in vivo lipid peroxidation, as measured by plasma F2-isoprostane concentrations. We investigated this association in a subset of the participants in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Of 256 male participants, a subsample of 100 consecutive men was selected for F2-isoprostane assays. The mean tHcy was 11.0 micromol/L, and the mean F2-isoprostanes was 29.6 ng/L. The simple correlation coefficient for association between tHcy and F2-isoprostane was 0.40 (P<0.001). In a linear regression model, the variables with the strongest associations with F2-isoprostane were tHcy (standardized coefficient 0.33, P<0.001), serum triglycerides (0.21, P=0.042), carbohydrate-deficient transferrin (0.15, P=0.132), and plasma lipid-standardized alpha-tocopherol (-0.11, P=0.252) (R2=0.24, P<0. 001 for model). Plasma F2-isoprostane levels increased linearly across quintiles of tHcy (P<0.001). The unadjusted mean (95% confidence interval) F2-isoprostanes was 47.5% greater in the highest tHcy quintile (37.4, 31.1 to 43.6 ng/L) than in the lowest quintile (25.3, 21.3 to 29.3 ng/L). Adjustment for the strongest other determinants of F2-isoprostane reduced this difference to 28. 2% (P=0.010). Our present data suggest that elevated fasting plasma tHcy is associated with enhanced in vivo lipid peroxidation in men.

Topics: Arteriosclerosis; Ascorbic Acid; beta Carotene; Dinoprost; Double-Blind Method; Fasting; Humans; Hyperhomocysteinemia; Linear Models; Lipid Peroxidation; Male; Middle Aged; Risk Factors; Transferrin; Triglycerides; Vitamin E

Homocysteine is increasingly recognized as a risk factor for atherothrombotic arterial diseases. We investigated the relation between plasma concentrations of total homocysteine (tHcy) and common carotid artery intima-media wall thickness, measured by B-mode ultrasonography, in 513 asymptomatic men and women from eastern Finland aged 45-69 years. The subjects were examined in 1994-95 at the baseline of the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study, a randomized double-blind placebo-controlled two by two factorial trial on the effect of vitamin E and C supplementation in the prevention of atherosclerotic progression. The subjects were assigned into two categories according to the plasma tHcy concentration; concentration over 11.5 micromol/L (highest quartile) or concentration below 11.5 micromol/L. In this study population the mean plasma tHcy concentration was 10.0 micromol/L, and the prevalence of plasma tHcy concentration exceeding 11.5 micromol/L was 33% in men and 18% in women. The adjusted mean intima-media thickness of the right and left common carotid arteries was 1.12 mm in men with elevated plasma tHcy concentration and 1.02 mm in men with a plasma tHcy concentration below 11.5 micromol/L (P = 0.029). In women there was no significant difference. We conclude that elevated plasma tHcy concentrations are associated with early atherosclerosis, as manifested by increased common carotid artery intima-media wall thickness, in middle-aged eastern Finnish men.

Topics: Adult; Aged; Arteriosclerosis; Ascorbic Acid; Carotid Artery Diseases; Carotid Artery, Common; Double-Blind Method; Female; Homocysteine; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Risk Factors; Smoking; Ultrasonography; Vitamin E

Evidence from observational epidemiologic studies has indicated that antioxidants consumed through the diet or as dietary supplements lower the risk of developing atherosclerotic cardiovascular disease. Evidence suggesting that the major mechanism for the protective effect of antioxidants is mediated through decreased oxidation of lipids, particularly low-density lipoprotein (LDL) cholesterol is accumulating. Other evidence, however, suggests that antioxidants may influence traditional modifiable cardiovascular risk factors such as the blood pressure and serum lipids favorably. The purpose of this study was to determine the effect of antioxidant vitamin supplementation on modifiable risk factors for atherosclerotic cardiovascular disease.. A randomized, placebo-controlled, clinical trial of antioxidant vitamin supplementation, conducted at a single community-based clinical research center.. We assigned 297 retired teachers who were members of the Maryland Retired Teachers Association randomly to 2-4 months of dietary supplementation with placebo or combined antioxidant vitamin capsules providing 400 IU/day vitamin E, 500 mg/day vitamin C, and 6 mg/day beta-carotene. The outcome measures were the blood pressure, fasting serum total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, and fasting glucose.. After 2-4 months of supplementation the combined antioxidant supplement had had no significant effect on the systolic and diastolic blood pressures, fasting serum lipids (total cholesterol, high-density lipoprotein cholesterol, and LDL cholesterol) and fasting glucose, with unadjusted and adjusted analyses.. Data from this trial suggest that the protective effect from antioxidant vitamin supplementation, if there is one, likely results from mechanisms other than modification of traditionally modifiable cardiovascular risk factors.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Lipids; Male; Middle Aged; Pilot Projects; Risk Factors; Time Factors; Vitamin E

The role of oxidative stress in the development of arteriosclerosis is well established. This pathogenetic explanation unificates in itself the lipid and thrombotic theories. The authors summarize the most substantial literary data in this relation, they discuss in details those therapic methods, in which the natural and synthetic antioxidants are involved as preventive drugs in the development and consequences of arteriosclerosis. Thus the effects of the dihydroquinoline type antioxidants as well as those of Vitamins A, C and E are discussed partly in experimental, partly in clinical studies. The authors conclude on the basis of own and literary data that the application of antioxidants could decrease the blood vessel alterations produced by arteriosclerosis, as well as the pathological tissue alterations developed in the consequences of ischaemia.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Free Radical Scavengers; Humans; Oxidative Stress; Quinolines; Vitamin A; Vitamin E

The oxidative modification of human low density lipoprotein (LDL) has been widely investigated. However, there are no data concerning the oxidation susceptibility of combined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein fraction, although all of them are atherogenic and contain antioxidants such as alpha-tocopherol. We investigated the oxidation susceptibility and oxidation resistance of VLDL + LDL (including IDL) fraction by induction with CuCl2 and its relation to plasma alpha-tocopherol concentration and lipid standardised alpha-tocopherol concentration in 406 non-vitamin E-supplemented men from eastern Finland. Even thought we did not give oral vitamin E or any other antioxidant supplementation to our study participants, we observed a significant, consistent relationship between measurements of oxidation resistance and plasma content of vitamin E. In the multivariate regression model, a high plasma content of vitamin E or lipid standardised vitamin E concentration were the most important determinants of lag time to maximal oxidation rate (standardised regression coefficient = 0.244, P < 0.0001 for vitamin E and 0.211, P < 0.0001 for lipid standardised vitamin E). After statistical adjustment for age, use of cigarettes, hypolipidemic medication (yes vs. no), month of the measurements, plasma concentrations of total ascorbic acid (ascorbic acid + dehydroascorbic acid), beta-carotene and phospholipids, serum concentrations of LDL cholesterol and triglycerides and dietary intake of linoleic acid, the lag time to maximal oxidation rate was 10% (95% C.I. 6.0-13.5%) longer in men in the highest fifth than in the lowest fifth of plasma vitamin E content (P < 0.0001 for trend). When the fifths of lipid standardised vitamin E were compared, the lag time to maximal oxidation rate was 6% (95% C.I. 1.8-10.1%) longer in men in the highest than in the lowest fifth (P < 0.0001 for trend). Our data suggest that alpha-tocopherol is an important antioxidant preventing the in vitro oxidation of VLDL + LDL fraction even in non-supplemented subjects.

Topics: Adult; Anticholesteremic Agents; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Cholesterol, LDL; Copper; Dietary Fats; Double-Blind Method; Humans; Hypercholesterolemia; Linoleic Acid; Linoleic Acids; Lipids; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Middle Aged; Oxidation-Reduction; Pravastatin; Risk Factors; Smoking; Vitamin E

The oxidative modification of low density lipoprotein (LDL) may play a role in the pathogenesis of atherosclerosis. Furthermore, evidence of oxidized LDL (ox-LDL) has been found in vivo. Supplementation of some animal models with antioxidants has been shown to retard the formation of aortic atherosclerosis. Ascorbate (vitamin C) is a highly potent aqueous-phase antioxidant in plasma, which has been shown in vitro to retard LDL oxidation. Cigarette smokers have reduced concentrations of ascorbate in their plasma, and their LDL may be more prone to oxidation. Hence, the objective of the present study was to examine the effect of ascorbate depletion and supplementation on the propensity of LDL to oxidize in smokers in a 6-week study. Nineteen healthy smokers followed a low ascorbate diet (< or = 30 mg/day) for 2 weeks, then were randomly assigned to receive placebo or 1000 mg ascorbate per day for 4 weeks. Blood was taken at 0 and 4 weeks of supplementation for study of LDL oxidative susceptibility. LDL was oxidized with 5 mumol/l copper. The ascorbate-supplemented group had significant increases in plasma ascorbate. The placebo group showed no change in the time course of LDL oxidation between 0 and 4 weeks. However, the ascorbate-supplemented group has a significant reduction in LDL oxidative susceptibility as measured by thiobarbituric acid-reactive substances (TBARS) and the formation of conjugated dienes. The ascorbate-supplemented group demonstrated significantly increased lag phase and decreased oxidation rate at 4 weeks compared to 0 weeks. No changes were found in the placebo group. The ascorbate-supplemented group showed no biochemical signs consistent with increased body iron stores. Supplementation of otherwise healthy smokers for 4 weeks with 1000 mg ascorbate per day resulted in increased plasma ascorbate and reduced LDL oxidative susceptibility.

Topics: Adult; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Cholesterol; Female; Free Radicals; Humans; Lipid Peroxidation; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Smoking; Thiobarbituric Acid Reactive Substances; Vitamin E

There is accumulating experimental, epidemiological, and clinical evidence of an association between anti-oxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis.. CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of > or = 100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of > or = 250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P = .03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found.. Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

Topics: Adult; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotid Arteries; Cholesterol; Disease Progression; Humans; Male; Middle Aged; Tunica Intima; Tunica Media; Ultrasonography; Vitamin E

Oxidation of low-density lipoprotein (LDL) may play a causal role in atherosclerosis. In this study we analyzed whether the severity of progression of coronary atherosclerosis is related to the susceptibility of LDL to oxidative modification. On the basis of repeated coronary angiography, 28 coronary bypass patients were divided into two groups: group A, 12 patients with, and group B, 16 patients without progression of coronary atherosclerosis. The lag time, reflecting the resistance of LDL to oxidative modification, was significantly smaller in group A as compared with group B (81 +/- 10 and 93 +/- 15 min, respectively). Besides differences in cholesterol and apolipoprotein B concentrations, the difference in susceptibility of LDL to oxidation significantly contributes to the differences between the progression and the non-progression group (P = 0.02). In the combined groups of patients, the lag phase of LDL for oxidation was positively correlated with LDL cholesterol ester to protein ratio (r = 0.53, P = 0.01). It is concluded that LDL samples obtained from coronary bypass patients differ with respect to their oxidizability depending on progression of atherosclerosis following coronary bypass surgery.

Topics: Apolipoproteins; Arteriosclerosis; Ascorbic Acid; Centrifugation, Density Gradient; Coronary Artery Bypass; Disease Progression; Follow-Up Studies; Humans; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Triglycerides; Vitamin E

Data continue to accumulate supporting a proatherogenic role for oxidized low-density lipoprotein (Ox-LDL). Antioxidant micronutrients such as ascorbate, alpha-tocopherol, and beta carotene, levels of which can be favorably manipulated by dietary measures without side effects, could be a safe approach in inhibiting LDL oxidation. In fact, in vitro studies have shown that all three antioxidants can inhibit LDL oxidation. The present study was undertaken to ascertain both the safety and antioxidant effect of combined supplementation with alpha-tocopherol, ascorbate, and beta carotene on LDL oxidation.. The effect of combined supplementation with alpha-tocopherol (800 IU/d) plus ascorbate (1.0 g/d) and beta carotene (30 mg/d) on copper-catalyzed LDL oxidation was tested in a randomized, placebo-controlled study in two groups of 12 male subjects over a 3-month period. Blood samples for the lipoprotein profile, antioxidant levels, and LDL isolation were obtained at baseline and at 3 months. Neither placebo nor combined antioxidant therapy resulted in any side effects or exerted an adverse effect on the plasma lipoprotein profile. Compared with placebo, combined antioxidant therapy resulted in a significant increase in plasma ascorbate and lipid standardized alpha-tocopherol and beta carotene levels (2.6-, 4.1-, and 16.3-fold, respectively). At baseline, there were no significant differences in the time course curves and kinetics of LDL oxidation as evidenced by the thiobarbituric acid reacting substances (TBARS) assay and the formation of conjugated dienes. However, at 3 months, combined supplementation resulted in a twofold prolongation of the lag phase and a 40% decrease in the oxidation rate. The combined antioxidant group was also compared with a group that received 800 IU of alpha-tocopherol only. Although the combined antioxidant group had significantly higher ascorbate and beta carotene levels than the group supplemented with alpha-tocopherol alone, there were no significant differences between the two groups with respect to LDL oxidation kinetics.. Combined supplementation with ascorbate, beta carotene, and alpha-tocopherol is not superior to high-dose alpha-tocopherol alone in inhibiting LDL oxidation. Hence, alpha-tocopherol therapy should be favored in future coronary prevention trials involving antioxidants.

Topics: Adult; Arteriosclerosis; Ascorbic Acid; beta Carotene; Carotenoids; Diet; Drug Synergism; Humans; Kinetics; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Thiobarbituric Acid Reactive Substances; Vitamin E

The aim of the study was to establish whether it is possible, in a group of deliberately selected subjects with hyperlipidaemia, to modulate cholesterol levels by ascorbic acid administered at a dose of 500 mg/day. The authors assessed the levels of vitamin C, total and HDL cholesterol, triacylglycerols in the blood serum of 140 probands assigned to an 83-member experimental group, and to a 57-member control group. The experimental group was provided Celaskon effervescens Spofa at a dose of 500 mg/day/person. The experiment lasted for 18 months. Blood collections were made in the whole cohort at six-month intervals. Administration of L-ascorbic acid led to a highly significant decrease in the levels of total and LDL cholesterol. After 12 months of study, a highly significant decrease in atherogenic index and an increase in HDL cholesterol levels were found persisting until the end of the experiment.

Topics: Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Lipids; Lipoproteins; Male; Middle Aged; Triglycerides

Forty patients with past history myocardial infarction were divided into three groups. Group I served as controls, while Groups II and III were given respectively, 1 g and 2 g vitamin C daily, divided in two doses. Samples were collected initially, and then every 2 months during the 6-month period of vitamin C administration and finally 2 months after stopping vitamin C. Vitamin C, 0.5 g twice daily (Group II), increased serum ascorbic acid by about 22% (P less than 0.05). However, no significant changes were observed in fibrinolytic activity or blood lipids. When the dose of vitamin C was doubled, serum ascorbic acid increased by about 96% and fibrinolytic activity increased by 45% (P less than 0.01), while the platelet adhesive index decreased by 27% (P less than 0.01). The serum cholesterol level dropped by 12% (P less than 0.05) and a significant decrease in serum beta lipoproteins and an increase in the alpha fraction was also seen. A further 40 patients with acute myocardial infarction were divided into two groups; one received 2 g vitamin C daily for the first 20 days and the other received a placebo. Blood samples were collected every 10th day during the 40-day follow up. Vitamin C administration increased fibrinolytic activity by 62.5%, while serum ascorbic acid rose by 94%.

Topics: Acute Disease; Adult; Arteriosclerosis; Ascorbic Acid; Coronary Disease; Fibrinolysis; Humans; Lipids; Male; Middle Aged; Myocardial Infarction; Platelet Adhesiveness; Time Factors

Observation shows diabetic patients to be more prone to oxidative stress because of hyperglycemia. The elevation of free radical production by this hyperglycemic production may exacerbate cardiovascular complication in diabetes. This study aims to investigate the oxidative stress related parameters in type 2 DM. Since the effects of glycemic control and cardiovascular complications in DM on these parameters has been not fully determined, the comparison between plasma MDA (malondialdehyde) and antioxidant nutrients with their age-matched normal healthy group may be used to determine the susceptibility of oxidative stress in this type of DM.. MDA and antioxidant nutrients (vitamin A, C, E and beta-carotene) were analyzed in plasma of 19 subjects with poorly controlled type 2 DM (fasting plasma glucose [FPG] > 180 mg/dl), 26 subjects with fairly controlled type 2 DM (FPG < or = 180 mg/dl), and 20 subjects with type 2 DM complicated coronary heart disease (CHD) who were matched for age and gender. Twenty healthy subjects with normal plasma glucose level (FPG < 110 mg/dl) and matched for age and gender served as a control group. In all groups of DM these oxidative stress parameters were compared to a normal group.. The plasma MDA levels were significantly higher in all types of DM compared to age-matched normal control. Plasma antioxidant vitamin C and E significantly lower only in poorly controlled and CHD complicated type 2 DM, respectively. The mean of plasma vitamin E level was lowest in type 2 DM complicated with CHD. No significant differences in both plasma vitamin A and beta-carotene were noted between any types of DM and age-matched normal healthy group. The positive correlation between MDA and FPG was demonstrated in most group of patients with their normal subjects except in fairly controlled type 2 DM and negative correlation between vitamin E and FPG was also demonstrated in type 2 DM with CHD.. These findings suggested that diabetic patients were susceptible to oxidative stress and higher plasma glucose level had an association with free radical-mediated lipid peroxidation. The lowest level of vitamin E in type 2 DM complicated with CHD indicated that oxidative stress played an important role in cardiovascular complication and vitamin E supplementation may be necessary for treatment and prevention in this group of diabetics.

Topics: Adult; Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; Blood Glucose; Case-Control Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Lipid Peroxidation; Male; Middle Aged; Nutritional Status; Oxidative Stress; Risk Factors; Vitamin E

In the present study we investigate the effect of homocysteine (Hcy) administration, the main metabolite accumulating in homocystinuria, on butyrylcholinesterase (BuChE) activity in serum of rats. For the acute treatment, 29-day-old Wistar rats received one subcutaneous injection of Hcy (0.6 micromol/g) or saline (control) and were killed 1 h later. For the chronic treatment, Hcy was administered subcutaneously to rats from the 6th to the 28th day of life. Control rats received saline. The rats were killed 12 h after the last injection. In another set of experiments, rats were pretreated for one week with vitamins E and C or saline and 12 h after the last injection received one single injection of Hcy or saline, being killed 1 h later. Serum was used to determine BuChE activity. Our results showed that acute and chronic administration of Hcy significantly decreased BuChE activity. Furthermore, vitamins E and C per se did not alter BuChE activity, but prevented the reduction of this enzyme activity caused by acute administration of Hcy. The data suggest that the inhibitory effect of Hcy on BuChE activity is probably mediated by free radicals, since vitamins E and C administration prevented such effect.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Butyrylcholinesterase; Disease Models, Animal; Down-Regulation; Enzyme Activation; Free Radicals; Homocysteine; Homocystinuria; Hyperhomocysteinemia; Lipid Metabolism; Oxidative Stress; Rats; Rats, Wistar; Vitamin E

Oxidized low-density lipoproteins (LDL) play a central role in atherogenesis and induce expression of the antioxidant stress protein heme oxygenase 1 (HO-1). In the present study we investigated induction of HO-1 and adaptive increases in reduced glutathione (GSH) in human aortic smooth muscle cells (SMC) in response to moderately oxidized LDL (moxLDL, 100 microg protein/ml, 24 h), a species containing high levels of lipid hydroperoxides. Expression and activity of HO-1 and GSH levels were elevated to a greater extent by moxLDL than highly oxidized LDL but unaffected by native or acetylated LDL. Inhibitors of protein kinase C (PKC) or mitogen-activated protein kinases (MAPK) p38(MAPK) and MEK or c-jun-NH2-terminal kinase (JNK) significantly attenuated induction of HO-1. Phosphorylation of p38(MAPK), extracellular signal-regulated kinase (ERK1/2), or JNK and nuclear translocation of the transcription factor Nrf2 were enhanced following acute exposure of SMC to moxLDL (100 microg protein/ml, 1-2 h). Pretreatment of SMC with the antioxidant vitamin C (100 microM, 24 h) attenuated the induction of HO-1 by moxLDL. Native and oxidized LDL did not alter basal levels of intracellular ATP, mitochondrial dehydrogenase activity, or expression of the lectin-like oxidized LDL receptor (LOX-1) in SMC. These findings demonstrate for the first time that activation of PKC, p38(MAPK), JNK, ERK1/2, and Nrf2 by oxidized LDL in human SMC leads to HO-1 induction, constituting an adaptive response against oxidative injury that can be ameliorated by vitamin C.

Topics: Active Transport, Cell Nucleus; Adenosine Triphosphate; Antioxidants; Arteriosclerosis; Ascorbic Acid; Blotting, Western; Cell Survival; Cells, Cultured; DNA-Binding Proteins; Endothelium, Vascular; Enzyme Inhibitors; Glutathione; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Hydrogen Peroxide; Lectins; Lipid Metabolism; Lipoproteins, LDL; MAP Kinase Signaling System; Membrane Proteins; Microscopy, Fluorescence; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocytes, Smooth Muscle; NF-E2-Related Factor 2; Oxygen; p38 Mitogen-Activated Protein Kinases; Time Factors; Trans-Activators

The objective of this study was to evaluate the influence of ingested l-arginine, l-citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a high-cholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo, the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with l-arginine, l-citrulline, and/or antioxidants. l-arginine plus l-citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma NO(2)(-)+NO(3)(-) and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including l-arginine, l-citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans.

Topics: Animals; Antioxidants; Aorta, Thoracic; Arginine; Arteriosclerosis; Ascorbic Acid; Citrulline; Cyclic AMP Response Element-Binding Protein; Cyclic GMP; Diet, Atherogenic; DNA-Binding Proteins; Endothelium, Vascular; ets-Domain Protein Elk-1; Humans; Male; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Oxidation-Reduction; Proto-Oncogene Proteins; Rabbits; Superoxides; Transcription Factors; Vasodilation; Vitamin E

Hypercholesterolemia (HC) and atherosclerosis can elicit oxidative stress, coronary endothelial dysfunction, and myocardial ischemia, which may induce growth-factor expression and lead to myocardial neovascularization. We tested the hypothesis that chronic antioxidant intervention in HC would attenuate neovascularization and preserve the expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF).. Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet or HC+antioxidant supplementation (100 IU/kg vitamin E and 1 g vitamin C daily). Myocardial samples were scanned ex vivo with a novel 3D micro-CT scanner, and the spatial density and tortuosity of myocardial microvessels were determined in situ. VEGF mRNA, protein levels of VEGF and VEGF receptor-1, HIF-1alpha, nitrotyrosine, and superoxide dismutase (SOD) were determined in myocardial tissue. The HC and HC+antioxidant groups had similar increases in serum cholesterol levels. HC animals showed an increase in subendocardial spatial density of microvessels compared with normal (160.5+/-11.8 versus 95.3+/-8.2 vessels/cm2, P<0.05), which was normalized in HC+antioxidant (92.5+/-20.5 vessels/cm2, P<0.05 versus HC), as was arteriolar tortuosity. In addition, HC induced upregulation of VEGF, HIF-1alpha, and nitrotyrosine expression and decreased SOD expression and activity, all of which were preserved by antioxidant intervention.. Changes in myocardial microvascular architecture invoked by HC are accompanied by increases in HIF-1alpha and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiotonic Agents; Coronary Circulation; Diet, Atherogenic; Dinoprost; Enzyme Induction; Female; Gene Expression Profiling; Gene Expression Regulation; Heart; Hypercholesterolemia; Hypoxia-Inducible Factor 1, alpha Subunit; Imaging, Three-Dimensional; Myocardial Ischemia; Neovascularization, Pathologic; Oxidative Stress; Superoxide Dismutase; Swine; Tomography, X-Ray Computed; Transcription Factors; Tyrosine; Vascular Endothelial Growth Factor A; Vitamin E

The potential protective effect of vitamins C and E against the development of diabetic retinopathy has not been thoroughly evaluated in epidemiologic studies.. The objective was to study the association between prevalent diabetic retinopathy and intake of vitamins C and E in participants of the Atherosclerosis Risk in Communities Study.. A total of 1353 subjects with type 2 diabetes diagnosed between 1993 and 1995 or before were included. Nutrient intake was assessed with a food-frequency and supplement questionnaire administered between 1987-1989 and 1993-1995. Prevalent retinopathy (n = 224) was determined in 1993-1995 from graded fundus photographs.. No association of retinopathy with intake of vitamin C or E from food alone or from food and supplements combined was observed. The odds ratios and 95% CIs for retinopathy for quartile 4 compared with quartile 1 of vitamins C and E intakes from food and supplements combined were 1.1 (0.7, 1.9) and 1.3 (0.8, 2.2), respectively, after adjustment for diabetes treatment and serum glucose. There was a significant interaction of the observed relations with serum glucose concentration (P < 0.05). Additionally, a decreased odds of retinopathy was found among users (reported use > or =3 y before 1993-1995) of vitamin C or E supplements or multisupplements compared with reported use of no supplements: 0.5 (0.3, 0.8), 0.5 (0.2, 0.8), and 0.4 (0.2, 0.9), respectively.. No significant overall associations were observed between risk of retinopathy and intake of major dietary antioxidants. The observed association between risk of retinopathy and supplement use may reflect nondietary factors or a possible benefit of supplementation.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diet; Dietary Supplements; Epidemiologic Studies; Female; Health Surveys; Humans; Male; Middle Aged; Nutrition Surveys; Odds Ratio; Prevalence; Risk Factors; Surveys and Questionnaires; Vitamin E

The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention (l-arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and l-arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with l-arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.

Topics: Animals; Antioxidants; Arginine; Arteriosclerosis; Ascorbic Acid; Diet, Atherogenic; Hyperlipoproteinemia Type II; Male; Mice; Mice, Knockout; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Physical Conditioning, Animal; Receptors, LDL; Vitamin E

BO-653, 2,3-dihydro-5-hydroxy-4,6-di-tert-butyl-2,2-dipentylbenzofuran, is a synthetic antioxidant which is now being developed as an anti-atherogenic drug. The antioxidant action of BO-653 against lipid peroxidation in rat plasma was studied and compared with its analogue BO-653M, 2,3-dihydro-5-hydroxy-4,6-di-methyl-2,2-dipentylbenzofuran, and vitamin E. BO-653 was readily incorporated into plasma by oral administration and it inhibited plasma lipid peroxidation more efficiently than vitamin E independent of the presence or absence of vitamin C. On the other hand, its analogue BO-653M having two methyl substituents in place of tert-butyl groups of BO-653 did not inhibit the lipid peroxidation in plasma as efficiently as BO-653, demonstrating clearly that the tert-butyl groups at the ortho-position play a key role in determining the antioxidant efficacy.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Benzofurans; Lipid Peroxidation; Male; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Vitamin E

A new class of NO-donor phenol derivatives is described. The products were obtained by joining appropriate phenols with either nitrooxy or 3-phenylsulfonylfuroxan-4-yloxy moieties. All the compounds proved to inhibit the ferrous salt/ascorbate induced lipidic peroxidation of membrane lipids of rat hepatocytes. They were also capable of dilating rat aorta strips precontracted with phenylephrine.

Topics: Animals; Antioxidants; Aorta; Arteriosclerosis; Ascorbic Acid; Ferrous Compounds; Hepatocytes; Hypolipidemic Agents; Lipid Peroxidation; Male; Membrane Lipids; Nitric Oxide Donors; Phenols; Phenylephrine; Rats; Rats, Wistar; Structure-Activity Relationship; Thiobarbituric Acid Reactive Substances

In cultured endothelial cells, the antioxidant, L-ascorbic acid (vitamin C), increases nitric oxide synthase (NOS) enzyme activity via chemical stabilization of tetrahydrobiopterin. Our objective was to determine the effect of vitamin C on NOS function and tetrahydrobiopterin metabolism in vivo. Twenty-six to twenty-eight weeks of diet supplementation with vitamin C (1%/kg chow) significantly increased circulating levels of vitamin C in wild-type (C57BL/6J) and apolipoprotein E (apoE)--deficient mice. Measurements of NOS enzymatic activity in aortas of apoE-deficient mice indicated a significant increase in total NOS activity. However, this increase was mainly due to high activity of inducible NOS, whereas eNOS activity was reduced. Significantly higher tetrahydrobiopterin levels were detected in aortas of apoE-deficient mice. Long-term treatment with vitamin C restored endothelial NOS activity in aortas of apoE-deficient mice, but did not affect activity of inducible NOS. In addition, 7,8-dihydrobiopterin levels, an oxidized form of tetrahydrobiopterin, were decreased and vascular endothelial function of aortas was significantly improved in apoE-deficient mice. Interestingly, vitamin C also increased tetrahydrobiopterin and NOS activity in aortas of C57BL/6J mice. In contrast, long-term treatment with vitamin E (2000 U/kg chow) did not affect vascular NOS activity or metabolism of tetrahydrobiopterin. In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity.

Topics: Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Ascorbic Acid; Biopterins; Cyclic AMP; Cyclic GMP; Dietary Supplements; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; In Vitro Techniques; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Superoxides; Time; Tyrosine; Vasomotor System; Vitamin E

Topics: alpha-Tocopherol; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Carotid Artery Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Endpoint Determination; Female; Humans; Male; Oxidative Stress; Vitamin E

Degradation of extracellular matrix, particularly interstitial collagen, promotes plaque instability and contributes to restenosis after vascular injury. We have explored the effects of vitamins C and E on the collagen content and metalloproteinase-1 (MMP-1) expression after angioplasty in hypercholesterolemic pigs. Iliac angioplasty was performed on 18 minipigs divided into three diet groups: a normal-cholesterol (NC), a high-cholesterol (HC) and a high-cholesterol plus vitamins C+E (HCV). Four weeks later, after sacrifice, the vascular collagen content and MMP-1 protein expression, along with the plasma caseinolytic activity and lipid peroxidation, were measured. MMP-1 was also determined in arterial rings stimulated with native low-density lipoproteins (LDL) isolated from experimental groups. Cholesterol-rich diet augmented plasma lipid peroxidation (P<0.05), reduced the collagen content and increased vascular MMP-1 expression after injury (P<0.05). Enhanced caseinolytic activity (identified as MMP-1) was also observed in HC plasma samples and in supernatants from arterial rings incubated with HC-LDL. Vitamins C and E markedly increased neointimal collagen content (P<0.01), reduced the hypercholesterolemia-induced changes in vascular MMP-1 (P<0.05) and diminished plasma and ex vivo caseinolytic activity. Vitamins C and E may help stabilize atherosclerotic plaque after angioplasty and favor vascular remodeling by increasing collagen content and reducing vascular MMP-1 expression in porcine hypercholesterolemia.

Topics: Analysis of Variance; Angioplasty; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Disease Models, Animal; Hypercholesterolemia; Iliac Artery; Lipid Peroxidation; Matrix Metalloproteinase 1; Probability; Sensitivity and Specificity; Swine, Miniature; Vitamin E

It has been proposed that plasma low density lipoproteins (LDL) undergo oxidative modification before they can produce foam cells in atherosclerosis. The oxidation of LDL generates a variety of reactive aldehydic products, which covalently bind to the LDL apolipoprotein B-100 (apoB). In the present study, to investigate the mechanisms contributing to the modification of LDL, we analyzed oxidized cholesteryl esters generated during the autoxidation of LDL and characterized their covalent binding to the lysine residues of LDL apoB. In addition, we raised a monoclonal antibody specific to a lysine-bound oxidized cholesteryl ester and determined its production in human atherosclerotic lesions. The peroxidation of LDL with Cu2+ produced 9-oxononanoylcholesterol (9-ONC) and 5-oxovaleroylcholesterol as the major oxidized cholesteryl esters. We observed that the levels of 9-ONC and 5-oxovaleroylcholesterol peaked at 12 h and significantly decreased thereafter. The reduction of the core aldehyde levels was accompanied by (i) the formation of free 7-ketocholesterol and 7-ketocholesteryl ester core aldehydes and (ii) an increase in the amounts of apoB-bound cholesterol and 7-ketocholesterol, suggesting that the cholesteryl ester core aldehydes were further converted to their 7-ketocholesterol- and apoB-bound derivatives. To detect the protein-bound 9-ONC, we raised the monoclonal antibody 2A81, directed against 9-ONC-modified protein, and found that it extensively recognized protein-bound cholesteryl ester core aldehydes. Agarose gel electrophoresis followed by immunoblot analysis of the oxidized LDL clearly demonstrated the formation of antigenic structures. Furthermore, immunohistochemical analysis of the atherosclerotic lesions from the human aorta showed that immunoreactive materials with mAb 2A81 were indeed present in the lesions, in which the intense immunoreactivity was mainly located in the macrophage-derived foam cells and the thickening neointima of the arterial walls. The results of this study suggest that the binding of cholesteryl ester core aldehydes to LDL might represent the process common to the oxidative modification of lipoproteins.

Topics: Aldehydes; Antibodies, Monoclonal; Aorta; Apolipoprotein B-100; Apolipoproteins B; Arteriosclerosis; Ascorbic Acid; Autoantigens; Cholesterol; Cholesterol Esters; Cholesterol, LDL; Humans; Iron; Ketocholesterols; Lipid Peroxidation; Lipoproteins, LDL; Lysine; Oxidation-Reduction; Schiff Bases

Disodium ascorbyl phytostanyl phosphate (FM-VP4) consists of ascorbic acid covalently bound to phytostanols by a phosphodiester linkage and is derived as the disodium salt. The purpose of this study was to evaluate the lipid-lowering and antiatherosclerotic properties of FM-VP4 following administration to apolipoprotein E (ApoE)-deficient mice. Four-week-old male C57BL/6J mice with a homozygous deletion of the ApoE gene (apolipoprotein E knock-out) were administered 0 (control), 0.1%, 0.5%, 1.0%, and 2.0% (wt/vol) FM-VP4 in their drinking water or 2.0% FM-VP4 (wt/wt) in their diet for 12 consecutive weeks. All animals received a standard mouse chow diet consisting of 9.0% (wt/wt) fat and 0.2% (wt/wt) cholesterol. Plasma cholesterol and triglyceride levels were determined at baseline and at 4-week intervals (4, 8, and 12 weeks) throughout the term of the study. At the end of the study, mice were killed using CO(2) gas, and blood was taken from the heart. The heart and aorta were removed and sections of the aortic roots were stained with oil red O (ORO) and Movat's stain. The lesions found in this area were measured using a computer-assisted image analysis. Consumption of FM-VP4 by either food or drinking water routes was associated with an approximately 75% reduction in total plasma cholesterol levels and a 75% decrease in aortic atherosclerotic lesion area in ApoE-deficient mice over 12 weeks compared to controls. A trend in decreasing plasma triglyceride levels was also observed. Taken together these data suggest that FM-VP4 has both lipid-lowering and antiatherosclerotic properties following 12-week administration to ApoE-deficient mice.

Topics: Animals; Anticholesteremic Agents; Apolipoproteins E; Arteriosclerosis; Ascorbic Acid; Cholesterol; Diet; Dose-Response Relationship, Drug; Histocytochemistry; Image Processing, Computer-Assisted; Male; Mice; Mice, Inbred C57BL; Phytosterols; Triglycerides

Antioxidant component alterations in the aorta during atherogenesis were examined in atherosclerosis-susceptible (SUS) Japanese quail fed a cholesterol-supplemented (0.5% w/w) diet. Birds fed a non-supplemented diet provided information on the effects of aging on endogenous antioxidants. One hundred adult SUS males were used. Birds were sacrificed after 0, 4, 8 and 12 weeks on the diets and were examined for plaque development and corresponding antioxidant component alterations in aorta and myocardium. With aging, superoxide dismutase (SOD) activity was increased in both tissues, whereas aortic glutathione peroxidase (GPx) activity and myocardial glutathione reductase (GRd) activity decreased. Myocardial ascorbate levels increased with aging, with a reciprocal decrease in myocardial tocopherol levels. Following 4 weeks of cholesterol supplementation, aortic GRd decreased, SOD activity increased, but activities of GPx and catalase were unchanged. This same qualitative pattern of antioxidant enzyme changes was also found in myocardium. Thus, although aortic antioxidant enzyme changes produced by cholesterol feeding and aging showed some similarities, the early phase of atherogenesis does not simply reflect accelerated aging. In the late stages of atherogenesis, SOD activity returned to baseline, but other antioxidant enzymes remained unaltered from levels characterizing the early phase of lesion development. There was no detectable functional coupling between changes in GPx and GRd, nor between SOD (which produces hydrogen peroxide) and GPx or catalase (which utilize hydrogen peroxide as substrate). Previously reported alterations in erythrocyte antioxidant enzyme components during atherogenesis in quail were not predictive of changes in the corresponding enzymes in the aorta and myocardium.

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Catalase; Coturnix; Glutathione Peroxidase; Male; Quail; Superoxide Dismutase; Tocopherols

Paraoxonase (PON1), an esterase physically associated with high density lipoprotein, has been shown to inhibit atherogenic low density lipoprotein and high density lipoprotein oxidation. PON1 activity appears to be primarily under genetic control with some environmental modification and is a predictor of vascular disease. Vitamins C and E, dietary antioxidants, scavenge free-oxygen radical products that may depress PON1 activity. Therefore, we evaluated the relationship between dietary vitamin C and E intake and PON1 activity.. The vitamin C and E intakes of male white subjects (n=189) were estimated by using a standardized food frequency survey. With covariates, vitamin C or E intakes were found to be significant positive predictors of PON1 activity for the hydrolysis of paraoxon and diazoxon with the use of linear regression. Smoking and use of statins were independent predictors of PON1 activity.. PON1 activity, which is primarily genotype dependent, varies with antioxidant vitamins, cigarette smoking, and statin drug use. Because PON1 activity is a better predictor of vascular disease than is the currently described genetic variation in PON1, further studies of the environmental influences on PON1 activity and additional PON1 genetic variants are warranted.

Topics: Aged; Aged, 80 and over; Arteriosclerosis; Aryldialkylphosphatase; Ascorbic Acid; Cholesterol, HDL; Cholesterol, LDL; Diet; Esterases; Genotype; Humans; Hypolipidemic Agents; Lipid Peroxidation; Male; Middle Aged; Smoking; Vitamin E

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Disease Progression; Humans; Organ Transplantation; Vitamin E

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Humans; Organ Transplantation; Vitamin E

It is well established that radical reaction of low density lipoprotein (LDL) causes fragmentation and cross-linkage of apolipoprotein B-100 (apoB). Our previous studies demonstrated that fragmented and cross-linked apoB proteins are present in normal human serum and tended to increase with age based on immunoblot analysis. These observations suggest that the fragmentation and cross-linkage pattern of apoB reflects the oxidative stress in an individual and that this pattern is a good atherosclerotic index. In this study, a method was developed to evaluate the fragmentation and conjugation pattern of apoB. A parameter named B-ox was introduced for each serum sample to quantitate the staining bands of the immunoblotting analysis. B-ox represents the relative abundance of radical reaction products (a sum of fragmented and conjugated apoB proteins) based on one control subject. If this value increases, it indicates that radical reaction products have increased, i.e., the oxidative stress has increased in the subject. Based on measurements of subjects in a rural area of Japan, B-ox showed significant positive correlation with intima-media thickness (IMT) of the carotid artery, LDL cholesterol, and age, while it showed significant negative correlation with high density lipoprotein (HDL) cholesterol and vitamin C. These results suggest that B-ox is a reliable indicator of atherosclerosis.

Topics: Aging; Apolipoprotein B-100; Apolipoproteins B; Arteriosclerosis; Ascorbic Acid; Biomarkers; Carotid Arteries; Female; Humans; Immunoblotting; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Ultrasonography; Vitamin E

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Biomarkers; Humans; Oxidative Stress; Patient Selection; Research Design; Vitamin E

Enhanced oxidative stress in haemodialysis (HD) patients may be considered as a risk factor for accelerated atherosclerosis. Reduced antioxidant defences include impairment in enzyme activities and decreased plasma levels of hydrophilic vitamin C (vit C), and cellular levels of lipophilic vitamin E (vit E).. We investigated plasma levels of vit C in 19 patients undergoing regular haemodiafiltration (HDF) (mean age 62+/-7 years) and in 1846 healthy elderly subjects (HS) (mean age 69+/-5 years). The contribution of convection and diffusion was determined using paired filtration dialysis (PFD), a modified HDF technique which physically separates convective from diffusive fluxes. Blood samples were collected before and after the HDF session; in addition at 60 min of HDF, samples were drawn from arterial lines (AL) and venous lines (VL), dialysate (D) and ultrafiltrate (UF). Blood levels of total vit C were determined using an HPLC fluorescence method. Markers of oxidative stress were also assessed in both populations as follows: levels of malondialdehyde (MDA) were determined by fluorometric assay, measurements of advanced oxidation protein products (AOPP) and glutathione peroxidase (GSH-Px) activity were performed by spectrophotometric assay, and plasma vit E content was obtained by an HPLC procedure.. A significant reduction in plasma vit C level was observed in HDF patients when compared with HS (1.6+/-1.4 microg/ml in HDF vs 6.6+/-3.7 microg/ml in HS; P<0.01). The HDF session was associated with a dramatic reduction in vit C levels (1.87+/-1.57 microg/ml before HDF and 0.98+/-0.68 microg/ml after HDF); at 60 min of HDF, concentrations were as follows: AL=1.35+/-1.27 microg/ml; VL=0.37+/-0.31 microg/ml, D=0.40+/-0.34 microg/ml, UF=1.24+/-1.18 microg/ml; corresponding to a diffusive flux of 271 microg/min and a convective flux of 126 microg/min. Total loss of vit C could be assessed at 66 mg/session (8--230 mg/session). According to this loss of vit C, presence of an oxidative stress was demonstrated in HD population as shown by a significant increase in MDA (1.66+/-0.27 microM in HD vs 0.89+/-0.25 microM in HS; P<0.01) and AOPP (77.5+/-29.3 microM in HD vs 23.5+/-13.2 microM in HS; P<0.01) levels, and a decrease in GSH-Px activity (259.2+/-106.3 U/l in HD vs 661.2+/-92.2 U/l in HS; P<0.01). No change in plasma vit E between both populations (30.7+/-9.1 microM in HD vs 35.3+/-7.34 microM in HS) was observed.. These results suggest that HDF with highly permeable membranes is associated with a significant loss of vit C. Diffusive transport is responsible for two-thirds whereas convective phenomenon accounts for only one-third of this loss.

Topics: Adult; Aged; Aged, 80 and over; Arteriosclerosis; Ascorbic Acid; Biomarkers; Blood Proteins; Case-Control Studies; Convection; Diffusion; Female; Glutathione Peroxidase; Hemodiafiltration; Humans; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Renal Dialysis; Risk Factors; Vitamin E

Atherosclerosis is a chronic disease which involves the build up of cholesterol and fatty deposits within the arterial wall. This results in the narrowing of the vessel lumen, which eventually restricts blood flow to vital organs such as the heart and lungs. These events may culminate in a heart attack or stroke, the commonest causes of death in the U.K. population. In this paper we study the early stages of atherosclerosis which include the build up of cholesterol within subendothelial cells to form what is known as a fatty streak, the earliest identifiable evidence of atherosclerosis. The deposition of cholesterol is believed to be a consequence of oxidation of circulating cholesterol-rich lipoproteins, in particular low density lipoproteins (LDLs). Via a mathematical model we investigate this process of oxidation within the context of an in vitro framework. We first recreate existing experimental results and then extend the model to investigate phenomenon not studied by current experimental protocols. We find that the model displays hysteresis which reveals some interesting insights into possible in vivo events. Mathematical analysis of this behaviour predicts that vitamin E supplementation is not as beneficial as high density lipoproteins (HDLs) and vitamin C. Furthermore, the scavenging of oxidants by HDL can provide an important first line of defence against LDL oxidation.

Topics: Arteriosclerosis; Ascorbic Acid; Computer Simulation; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Models, Biological; Oxidation-Reduction; Vitamin E

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Collagen; Disease Models, Animal; Disease Progression; Extracellular Matrix; Humans; Mice; Myocardial Infarction; Protein Processing, Post-Translational; Scurvy

Oxidative stress is thought to play an important role in atherogenesis, suggesting that antioxidants could prevent coronary artery disease. However, the efficacy of vitamin C in reducing atherosclerosis is debatable in humans and has not been tested rigorously in animals.. Gulo(-/-)Apoe(-/-) mice were used to test a hypothesis that chronic vitamin C deficiency enhances the initiation and development of atherosclerosis. These mice are dependent on dietary vitamin C because of the lack of L-gulonolactone-gamma-oxidase and are prone to develop atherosclerosis because of lacking apolipoprotein E. Beginning at 6 weeks of age, the Gulo(-/-)Apoe(-/-) mice were fed regular chow or Western-type diets containing high fat and supplemented with either 0.033 g or 3.3 g/L of vitamin C in their drinking water. This regimen produced mice with chronically low vitamin C (average 1.5 microg/mL in plasma) or high vitamin C (average 10 to 30 microg/mL in plasma). Morphometric analysis showed that within each sex, age, and diet group, the sizes of the atherosclerotic plaques were not different between low vitamin C mice and high vitamin C mice. However, advanced plaques in the low vitamin C mice had significantly reduced amounts of Sirius red-staining collagen (36.4+/-2.2% versus 54.8+/-2.3%, P<0.0001), larger necrotic cores within the plaques, and reduced fibroproliferation and neovascularization in the aortic adventitia.. Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.

Topics: Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Blood Glucose; Cholesterol; Cholesterol, HDL; Collagen; Crosses, Genetic; Dietary Fats; Dietary Supplements; Disease Models, Animal; Disease Progression; Female; L-Gulonolactone Oxidase; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Sex Factors; Sugar Alcohol Dehydrogenases; Triglycerides

Hypochlorous acid (HOCl), generated by myeloperoxidase released from activated macrophages, is thought to contribute to vascular dysfunction and oxidation of low density lipoproteins (LDLs) in atherogenesis. We have previously shown that HOCl exposure can cause chlorination and oxidation of isolated DNA and that vitamin C protects human arterial smooth muscle cells against oxidized LDL-mediated damage. We report in the present study that vitamin C attenuates HOCl-induced DNA base and protein damage and depletion of intracellular glutathione (GSH) and ATP in human arterial smooth muscle cells. Cells were pretreated in the absence or presence of 100 micromol/L vitamin C (24 hours) and then exposed to HOCl (0 to 500 micromol/L, 0 to 60 minutes) in the absence of vitamin C. Intracellular GSH and ATP levels were depleted by HOCl treatment, and gas chromatography-mass spectroscopy revealed a concentration- and time-dependent increase in DNA base oxidation and protein damage (measured as 3-chlorotyrosine). Pretreatment of smooth muscle cells with vitamin C significantly reduced the extent of HOCl-induced DNA and protein damage and attenuated decreases in intracellular ATP and GSH. Our findings suggest that physiological levels of vitamin C provide an important antioxidant defense against HOCl-mediated injury in atherosclerosis.

Topics: Adenosine Triphosphate; Arteriosclerosis; Ascorbic Acid; Cell Survival; Cells, Cultured; DNA; DNA Damage; Glutathione; Humans; Hypochlorous Acid; Muscle, Smooth, Vascular; Umbilical Arteries

Vitamin C and E are suggested to play a preventive role in the pathogenesis of atherosclerosis. They reduce oxidation of low density lipoproteins (oxLDL), thereby protecting human vascular arterial endothelial and smooth muscle cells from oxLDL induced damages.. Since vascular arterial endothelial and smooth muscle cells are both involved in atherosclerotic plaque formation, we simultaneously examined the effect of vitamin C, E and oxLDL on their DNA synthesis and proliferation to further elucidate their joint role in this process.. Human umbilical arterial endothelial cells (HUAEC) and human arterial smooth muscle cells (HUASMC) were incubated with "preventive concentrations" of vitamin C (60 microM) and E (30 microM) and with LDL (60 microg/ml) of increasing oxidation grade. Cell proliferation and DNA synthesis were determined by cell count and [3H]-thymidine uptake, respectively.. Vitamin C alone or in combination with E increased significantly cell number and [3H]-thymidine uptake in HUAEC. The combination exhibited the strongest effect. In contrast, cell number and [3H]-thymidine uptake in HUASMC were significantly decreased in the presence of vitamin C, vitamin E or its combination. OxLDL (60 microg/ml) inhibited cell number and [3H]-thymidine uptake in HUAECs, the latter in an oxidation-grade dependent manner. In HUASMC oxLDL promoted a higher cell number and [3H]-thymidine uptake. If induced by minimally oxLDL, this reduction or increase could be partially reversed by vitamin C alone or in combination with vitamin E.. Vitamin C and E, alone or in combination, modulate proliferation and DNA synthesis of human arterial endothelial and muscle cells and this modulation is antagonistic. Thus, vitamin C and E may act "preventive" on atherosclerotic plaque formation in two steps: first reendothelialisation is promoted, then HUASMC growth is inhibited.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Cell Count; Cells, Cultured; DNA; Endothelium, Vascular; Humans; In Vitro Techniques; Lipoproteins, LDL; Myocytes, Smooth Muscle; Thymidine; Umbilical Arteries; Umbilical Cord; Vitamin E

It has been reported that renovascular hypertension activates the renin-angiotensin system, leading to an increase in oxidative stress. We sought to determine whether renal-artery angioplasty improves endothelial dysfunction in patients with renovascular hypertension through a reduction in oxidative stress.. We evaluated the response of forearm blood flow to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after renal-artery angioplasty in 15 subjects with renovascular hypertension and 15 controls without hypertension who were matched for age and sex. Forearm blood flow was measured with the use of a mercury-filled Silastic strain-gauge plethysmograph.. The forearm blood flow in response to acetylcholine was less in subjects with renovascular hypertension than in controls, although the forearm blood flow in response to isosorbide dinitrate was similar in the two groups. Angioplasty decreased systolic and diastolic blood pressures, forearm vascular resistance, and urinary excretion of 8-hydroxy-2'-deoxyguanosine and serum malondialdehyde-modified low-density lipoprotein (LDL), indexes of oxidative stress. After angioplasty, the mean (+/-SD) forearm blood flow in response to acetylcholine was increased in the patients with renovascular hypertension (19.3+/-6.8 vs. 29.6+/-7.1 ml per minute per 100 ml, P=0.002). The increase in the maximal forearm blood flow in response to acetylcholine correlated significantly with the decrease in urinary excretion of 8-hydroxy-2'-deoxyguanosine (r=-0.51, P=0.004) and serum malondialdehyde-modified LDL (r=-0.39, P=0.02). Coinfusion of ascorbic acid (vitamin C) augmented the response of forearm blood flow to acetylcholine before angioplasty (P<0.001) but not after angioplasty.. These findings suggest that excessive oxidative stress is involved, at least in part, in impaired endothelium-dependent vasodilatation in patients with renovascular hypertension.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcholine; Adult; Angioplasty; Angiotensin II; Antioxidants; Arteriosclerosis; Ascorbic Acid; Biomarkers; Blood Pressure; Deoxyguanosine; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Fibromuscular Dysplasia; Forearm; Humans; Hypertension, Renovascular; Isosorbide Dinitrate; Lipoproteins; Male; Matched-Pair Analysis; Middle Aged; Oxidative Stress; Regional Blood Flow; Renal Artery; Vasodilation; Vasodilator Agents

It is well known that eating fruits and vegetables lowers the risk of chronic diseases such as heart disease and cancer. The question of what is/are the active ingredient(s) is still unresolved. The initial hypothesis was that the antioxidant vitamins were responsible. However, recently the polyphenols have been investigated since they have been found to have beneficial properties such as being strong antioxidants. We measured the polyphenol content of citrus juices by an oxidation-reduction colorimetric method (Folin) using catechin as the standard. The order was tangerine juice > grapefruit juice > orange juice. The antioxidant contribution of ascorbic acid was measured by the difference in Folin reactive content following removal by ascorbate oxidase. Ascorbate contributed 56 to 77% of the antioxidant content of orange juice, 46% of the single tangerine juice measured, and 66 to 77% of grapefruit juices. Polyphenol quality in the juices was analyzed by using the inhibition of lower density lipoprotein oxidation promoted by cupric ion, an in vitro model of heart disease. Quality decreased in the following order: orange juice > grapefruit juice > tangerinejuice. In orange juice polyphenols accounted for 84-85% of antioxidant quality. The pure polyphenol hesperidin, which is common in juices, ascorbic acid, and the citrus juices, were not able to bind with LDL+VLDL and protect it from oxidation. In a hamster model of atherosclerosis, the juices were able to significantly inhibit atherosclerosis and lowered cholesterol and triglycerides. Ascorbic acid alone in the dose provided by the juices was found to have the same effect on atherosclerosis. However, the polyphenols in the citrus

Topics: Adult; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Beverages; Citrus; Cricetinae; Diet, Atherogenic; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Female; Flavonoids; Heart Diseases; Hesperidin; Humans; Hypercholesterolemia; Hypertriglyceridemia; Lipids; Male; Mesocricetus; Middle Aged; Oxidation-Reduction; Phenols; Plant Extracts; Polymers; Species Specificity

Formation of an atherosclerotic lesion is in part mediated by inflammatory and oxidative mechanisms including lipid peroxidation. To characterize the potential role of lipid peroxidation products in atherogenesis, we assessed the effect of 4-hydroxy-2-nonenal (HNE), a component of oxidatively modified lipids on vascular smooth muscle cells (VSMCs) proliferation, and its interaction with serotonin (5-hydroxytryptamine, 5-HT), a known mitogen for VSMCs. Growth-arrested rabbit VSMCs were incubated with different concentrations of HNE in the absence or presence of 5-HT. VSMCs proliferation was examined by increases in [3H]thymidine incorporation into DNA and cell number. HNE and 5-HT stimulated DNA synthesis in a dose-dependent manner. HNE had a maximal proliferative effect at a concentration of 1 microM (143% of the control) and 5-HT at 50 microM (211%). When added together, low concentrations of HNE (0.1 microM) and 5-HT (5 microM) synergistically induced DNA synthesis (273%). These effects on DNA synthesis were paralleled by an increase in cell number. A 5-HT2 receptor antagonist LY 281067 (10 microg/ml) and pertussis toxin (10 ng/ml) inhibited the mitogenic effect of 5-HT only. Protein tyrosine kinase inhibitor erbstatin A (10 microM) completely inhibited the mitogenic effect of HNE and partially that of 5-HT and the combined effect of HNE+5-HT. Protein kinase C inhibitor Ro 31-8220 (0.1 microM) completely inhibited mitogenic effects of both HNE and 5-HT, and also the combined effect of HNE+5-HT. The synergistic effect of HNE+5-HT on DNA synthesis was completely reversed by the combined use of LY 281067 (10 microg/ml) and antioxidants N-acetylcysteine (400 microM), vitamin C (200 microM), or vitamin E (20 microM). Our results suggest that HNE acts synergistically with 5-HT in inducing VSMCs proliferation. Combined use of both antiplatelet and antioxidant therapies may be useful for the prevention of VSMCs proliferative disorders associated with atherosclerosis and restenosis after angioplasty.

Topics: Acetylcysteine; Aldehydes; Animals; Antioxidants; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Cell Division; Cells, Cultured; DNA; Dose-Response Relationship, Drug; Drug Synergism; Hydroquinones; Indoles; Lipid Peroxidation; Lysergic Acid; Male; Mitogens; Muscle, Smooth, Vascular; Pertussis Toxin; Protein Kinase C; Protein-Tyrosine Kinases; Rabbits; Serotonin; Serotonin Antagonists; Virulence Factors, Bordetella; Vitamin E

Peripheral arterial disease (PAD) is a severe atherosclerotic condition frequently accompanied by inflammation and oxidative stress. We hypothesized that vitamin C antioxidant levels might be low in PAD and are related to inflammation and disease severity.. We investigated vitamin C (L-ascorbic acid) levels in 85 PAD patients, 106 hypertensives without PAD, and 113 healthy subjects. Serum L-ascorbic acid concentrations were low among PAD patients (median, 27.8 micromol/L) despite comparable smoking status and dietary intake with the other groups (P<0.0001). Subclinical vitamin C deficiency (<11.4 micromol/L), confirmed by low serum alkaline phosphatase activity, was found in 14% of the PAD patients but not in the other groups. Serum C-reactive protein (CRP) concentrations were significantly higher in PAD patients (P<0.0001) and negatively correlated with L-ascorbic acid levels (r=-0.742, P<0.0001). In stepwise multivariate analysis, low L-ascorbic acid concentration in PAD patients was associated with high CRP level (P=0.0001), smoking (P=0.0009), and shorter absolute claudication distance on a standardized graded treadmill test (P=0.029).. Vitamin C concentrations are lower in intermittent claudicant patients in association with higher CRP levels and severity of PAD. Future studies attempting to relate vitamin C levels to disease occurrence should include in their analysis an inflammatory marker such as CRP.

Topics: Aged; Arteriosclerosis; Ascorbic Acid; Aspirin; C-Reactive Protein; Female; Fibrinogen; Humans; Hypertension; Inflammation; Lipids; Male; Middle Aged; Multivariate Analysis; Peripheral Vascular Diseases; Severity of Illness Index; Smoking

Peroxidatively modified low-density lipoprotein (LDL) may contribute to atherosclerotic processes; therefore, protecting LDL against peroxidation may thus reduce or retard the progression of atherosclerosis. We have evaluated the protective effects of ascorbic acid on copper-catalyzed LDL peroxidative modification. The protective effects of ascorbic acid on copper-catalyzed LDL peroxidative modification were examined by measurement of concentration of lipid hydroperoxides in LDL and by the provision of LDL cholesterol to lymphocytes via LDL receptor-mediated pathway. The measurement of concentration of lipid hydroperoxides in LDL showed that ascorbic acid inhibited peroxidative modification of LDL. Also, ascorbic acid preserved the ability of LDL to be recognized by LDL receptors in peripheral blood lymphocytes to the same extent as native LDL. These findings indicate that ascorbic acid may protect LDL against peroxidative modification, maintaining its ability to act as a ligand for LDL receptors in vivo.

Topics: Adult; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cells, Cultured; Cholesterol, LDL; Copper; Free Radical Scavengers; Humans; Ligands; Lipid Peroxidation; Lipid Peroxides; Lipoproteins, LDL; Lymphocytes; Receptors, LDL

In order to examine if organic acids (OA), a kind of natural food components, will prevent from atherosclerosis formation, the effects of four OA, namely chlorogenic acid (CHA), ascorbic acid (AA), citric acid (CA), and malic acid (MA) on human vascular endothelial cells were studied.. Primary human umbilical vein endothelial cells (EC) were cultured, and the changes of cell morphology, cell growth, lactate dehydrogenase (LDH) released from cells were measured when EC was incubated with oxidized low density lipoprotein (oxLDL) in the presence or not of four OA added at three different conditions, i.e. before 4 hours oxLDL added, at the same time as oxLDL added, and after 3 hours oxLDL added, as well as at the indicated doses (10, 20 or 40 mg/L).. The EC survival rate of the oxLDL control group was lower (P < 0.01) and LDH release rate was higher (P < 0.01) than those of normal control group. CHA, AA, CA and MA protected EC from damage caused by oxLDL when they were added before and/or at the same time of oxLDL, but the same beneficial effects of these four OA added after oxLDL were not observed. The EC survival rates of CHA + oxLDL and AA + oxLDL groups in three doses were higher (P < 0.05) and the LDH release rates were lower (P < 0.05) in a dose-effect manner when compared with those of oxLDL control group, respectively. Similar results were found in the CA + oxLDL and MA + oxLDL of the high dose groups.. Four tested OA could effectively prevent EC from damage induced by oxLDL. CHA and AA had the strongest effects, the next was CA, followed by MA.

Topics: Arteriosclerosis; Ascorbic Acid; Cells, Cultured; Chlorogenic Acid; Citric Acid; Endothelium, Vascular; Humans; Malates; Umbilical Veins

There are numerous data suggesting that oxidative stress may be involved in the development of atherosclerosis. Therefore, in the present study we measured the amount of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), one of the typical biomarkers of oxidative stress, in DNA isolated from lymphocytes of the patients and in the control group. Levels of antioxidant vitamins (A, C, and E) and intracellular labile iron pool (LIP), which can influence oxidative stress, were also determined. Blood samples were obtained from a control group of 55 healthy persons and from 43 atherosclerotic patients. 8-OH-dG and the vitamin levels were measured by high-performance liquid chromatography. Labile iron pool in lymphocytes was analyzed by fluorescent assay. The levels of 8-OH-dG and LIP were significantly higher and vitamin C concentration was significantly lower in the patient group than in the control group. The rest of the analyzed parameters do not significantly differ between the groups. A lower concentration of vitamin C and higher levels of labile iron pool in a group of atherosclerotic patients when compared with the control group may lead to oxidative stress, which is manifested by a higher level of 8-OH-dG in blood lymphocytes. All these factors may create an environment that promotes the development of atherosclerosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Arteriosclerosis; Ascorbic Acid; Biomarkers; Chromatography, High Pressure Liquid; Deoxyguanosine; Disease Progression; DNA; Female; Ferritins; Humans; Iron; Lymphocytes; Male; Middle Aged; Oxidative Stress; Risk Factors; Transferrin; Vitamin A; Vitamin E

Endothelial cell growth and reendothealization after vascular injury protect the vessel wall against endothelial dysfunction which is believed to play a major role in the pathogenesis of atherosclerosis.. of the study To investigate a possible protective role of antioxidant vitamins in the present study, the effect of vitamin E (alpha-tocopherol) alone and in combination with vitamin C on the DNA synthesis of human umbilical arterial endothelial cells (HUAEC) was examined. Furthermore, because oxidized low-density lipoprotein (ox-LDL) is thought to be involved in atherogenesis, the combined effect of vitamin E and vitamin C with ox-LDL and the influence of vitamin-pretreated LDL on HUAEC proliferation were investigated.. DNA-synthesis was determined by measurement of [3H]thymidine incorporation into the cell DNA.. Vitamin E alone and in combination with vitamin C resulted in an increase in [3H]thymidine incorporation into cell DNA, especially in the presence of basic fibroblast growth factor (bFGF). All vitamin-pretreated LDL samples and ox-LDL led to a nearly complete inhibition of endothelial DNA-synthesis. The ox-LDL-induced effect could not be prevented by vitamin E alone nor in combination with vitamin C.. It seems that once LDL oxidation is in process, vitamin E alone and in combination with vitamin C is ineffective to exert its antioxidative capacity under the conditions used. Thus, vitamin E alone and combined with vitamin C may act as antiatherogens by inducing endothelial cell growth.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Cells, Cultured; DNA; Endothelium, Vascular; Humans; Lipoproteins, LDL; Oxidation-Reduction; Umbilical Cord; Vitamin E

The effects of HDL, LDL and ascorbic acid on cultured human vascular endothelial gap junctional intercellular communication (GJIC) were observed using fluorescence recovery after photobleaching assay under confocal laser scanning microscopy in this study. The results showed that in culture, human vascular endothelial cells could produce functional gap junctions. The fluorescence recovery rates of the LDL group were 6.691 +/- 2.634, 4.153 +/- 2.125 and 2.441 +/- 0.720 respectively; when these rates were compared with the control and with each other, significant differences were found(P < 0.05). When the fluorescence recovery rates of the HDL group and Vitamin C group were compared with the control, no significant differences were found(P > 0.05). The fluorescence recovery rates of the LDL + HDL group were 3.500 +/- 0.890, 4.339 +/- 1.126 and 5.243 +/- 1.278(n = 15) respectively, when these rates were compared with the control and with each other, significant differences were found (P < 0.05). These suggested that LDL should be able to inhibit GJIC in human vascular endothelial cells, and the inhibition could be diminished by HDL or ascorbic acid. Inhibition of vascular endothelial GJIC may be one of the atherosclerogenic mechanisms of LDL, whereas HDL and ascorbic acid may be conducive to the improvement of endothelial GJIC. But it may also be only a compensatory behavior of endothelial cells to injuries.

Topics: Arteriosclerosis; Ascorbic Acid; Cell Communication; Cells, Cultured; Endothelium, Vascular; Gap Junctions; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Microscopy, Confocal

During passive smoking the body is attacked by an excess of free radicals inducing oxidative stress. In nonsmoking subjects even a short period of passive smoking breaks down serum antioxidant defense (TRAP) and accelerates lipid peroxidation leading to accumulation of their low-density lipoprotein (LDL) cholesterol in cultured human macrophages. We now studied whether these acute proatherogenic effects of secondhand smoke could be prevented by an effective free radical scavenger, vitamin C. Blood samples were collected from nonsmoking subjects (n = 10) as they were consecutively exposed to normal air or cigarette smoke during four separate days. During the last 2 d, a single dose of vitamin C (3 g) was given, which doubled its plasma concentration. Vitamin C did not influence the plasma antioxidant defense or the resistance of LDL to oxidation in normal air, but prevented the smoke-induced decrease in plasma TRAP (p <.001), the decrease in the resistance of LDL to oxidation (p <.05), and the accelerated formation of serum thiobarbituric acid reactive substances (TBARS) (p <.05) otherwise observed 1.5 h after the beginning of passive smoking. Vitamin C protected nonsmoking subjects against the harmful effects of free radicals during exposure to secondhand smoke.

Topics: Adult; Arteriosclerosis; Ascorbic Acid; beta Carotene; Female; Free Radicals; Humans; Lipid Peroxidation; Male; Middle Aged; Peroxides; Time Factors; Tobacco Smoke Pollution; Uric Acid; Vitamin A

Topics: Adult; Arteriosclerosis; Ascorbic Acid; Carotid Arteries; Diet Surveys; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Surveys and Questionnaires; Ultrasonography

Oxidative stress has been postulated to play important roles in the pathogenesis of various diseases such as atherosclerosis in hyperlipidemic subjects. Although the possible role of oxidation of low-density lipoprotein (LDL) in the etiology of atherosclerosis has been studied extensively, the turnover of endogenous antioxidants, which is an important protection system against oxidative stress, remains to be elucidated. The aim of our study was to determine the change of the turnover of endogenous antioxidants such as glutathione and ascorbic acid in case of hyperlipidemia, using Japanese white rabbits (JW) and Watanabe heritable hyperlipidemic rabbits (WHHL). The levels of total glutathione and low molecular weight thiols in the liver, kidney, and other organs in both strains of rabbits were similar. However, a kinetic analysis using L-buthionine-(S,R)-sulfoximine revealed that the rate of glutathione turnover in the liver and kidney of WHHL was about 50%) lower than that of JW. Furthermore, intravenously administered ascorbic acid disappeared more slowly in WHHL than in JW. These results indicate that the turnovers of both glutathione and ascorbic acid in WHHL are depressed in comparison with that in JW. These changes would be closely related to the increased oxidizability of lipids in the circulation of hyperlipidemic subjects.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Disease Models, Animal; Glutathione; Hyperlipidemia, Familial Combined; Kidney; Lipoproteins, LDL; Liver; Male; Oxidative Stress; Rabbits

Oxidatively modified low-density lipoprotein (LDL) has numerous atherogenic properties, and antioxidants that can prevent LDL oxidation may act as antiatherogens. We have previously shown that vitamin C (L-ascorbic acid, AA) and its two-electron oxidation product dehydro-L-ascorbic acid (DHA) strongly inhibit copper (Cu)-induced LDL oxidation. These findings are unusual, as AA is known to act not only as an antioxidant, but also a pro-oxidant in the presence of transition metal ions in vitro, and DHA has no known reducing capacity. Here we report that human LDL (0.4 mg protein/ml) incubated with 40 microM Cu2+ binds 28.0 +/- 3.3 Cu ions per LDL particle (mean +/- SD, n = 10). Co-incubation of LDL with AA or DHA led to the time- and concentration-dependent release of up to 70% of bound Cu, which was associated with the inhibition of LDL oxidation. Incubation of LDL with Cu and AA or DHA also led to the time-dependent formation of 2-oxo-histidine, an oxidized derivative of histidine with a low affinity for Cu. Addition of free histidine prevented the formation of the LDL-Cu complexes and inhibited LDL oxidation, despite the fact that Cu remained redox-active. Interestingly, histidine was more effective than AA or DHA at limiting Cu binding to LDL, but at low concentrations AA and DHA were more effective than histidine at inhibiting LDL oxidation. These data suggest that there are at least two types of Cu binding sites on LDL: those that bind Cu in a redox-active form critical for initiation of LDL oxidation, and those that bind Cu in a redox-inactive form not contributing to LDL oxidation. The former sites may be primarily histidine residues of apolipoprotein B-100 that are oxidized to 2-oxo-histidine in the presence of Cu and AA or DHA, thus explaining, at least in part, the unusual inhibitory effect of vitamin C on Cu-induced LDL oxidation.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Binding Sites; Copper; Dehydroascorbic Acid; Histidine; Humans; In Vitro Techniques; Lipid Peroxidation; Lipoproteins, LDL; Oxidation-Reduction; Protein Binding

Increased low-density lipoprotein (LDL) cholesterol is a recognized risk factor for atherosclerosis. There is also strong evidence that oxidatively modified LDL initiates the development of this pathological process and the administration of antioxidants might have a protective effect. However, the appropriate trials did not provide completely consistent results. We found in this study that the oxidation kinetics and also the antioxidant effectiveness are different depending on the cholesterol content in LDL. Higher cholesterol in LDL causes an acceleration of its oxidation as well as an increase of resistance to the antioxidative effect of ascorbic acid. In searching for a theoretical background of this dual impact of cholesterol in LDL, computer simulation of LDL oxidation was used. It was found that the pre-existing level of lipid hydroperoxides together with the total amount of oxidizable lipid substrate associated with the cholesterol level in LDL were satisfactory prerequisites for a best fit to the experimental data. In conclusion, this study provides at least a partial explanation for some failures to arrest, by administration of antioxidants, the progression of atherosclerosis in animal and human hypercholesterolemia.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, LDL; Computer Simulation; Humans; Hypercholesterolemia; Lipid Peroxides; Oxidation-Reduction

Oxidative stress, which occurs when there is excessive free-radical production or low antioxidant levels, makes significant contributions to pathogenesis in many human diseases. Cardiovascular disease is the major cause of mortality in patients receiving hemodialysis. For these patients, oxidative stress and increased lipid peroxidation may contribute to increased risk of atherosclerosis. The aim of this study was to determine if hemodialysis patients were associated with disturbance of homeostasis of antioxidant status. In this experiment, total antioxidant status of serum is measured by its ability to inhibit generation of free radicals from 2,2'-amino-di-[3-ethylbenzthiazole sulphonate] by metmyoglobin and hydrogen peroxide. Status of radical scavengers, such as serum total protein, albumin, uric acid and total bilirubin, was also measured. Blood were collected from three different episodes of hemodialysis. In the first group (n = 29), blood were collected before and after hemodialysis. In the second group (n = 29), blood were collected after dialysis and before next hemodialysis. In the third group (n = 8), blood were collected before hemodialysis. After last hemodialysis, patients started ingesting vitamin C and blood were collected before next hemodialysis. There was a marked reduction of total antioxidant status after hemodialysis in the first group. There was a marked increase in total antioxidant status before next hemodialysis in the second group. High doses of vitamin C caused increase in total antioxidant status in the third group. In conclusion, disturbance of homeostasis of total antioxidant status were observed in patients receiving hemodialysis. This may play a role in the pathogenesis in these groups.

Topics: Adult; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Female; Free Radical Scavengers; Homeostasis; Humans; Male; Middle Aged; Oxidative Stress; Renal Dialysis; Risk

Total CoQ10 levels were evaluated in whole blood and in plasma obtained from a group of 83 healthy donors. Extraction with light petroleum ether/methanol was more efficient, for whole blood, than the extraction which is often used for plasma and serum, i.e., ethanol hexane. An excellent correlation was present between plasma CoQ10 and whole blood CoQ10. CoQ10 is mainly associated with plasma rather than with cellular components. Positive, significant correlations were found between the LDL-chol/CoQ10 ratio and the total-chol/HDL-chol ratio, which is usually considered a risk factor for atherosclerosis. The proportion of CoQ10 carried by LDL was 58 +/- 10%, while the amount carried by HDL was 26 +/- 8%. In VLDL + IDL CoQ10 was 16 +/- 8%. The content of CoQ10 in single classes of lipoproteins is strictly correlated with CoQ10 plasma concentration. In a parallel study conducted on a population of diabetic patients (one IDDM group and one NIDDM) CoQ10 plasma levels were generally higher compared to the control group, also when normalised to total cholesterol. In particular the LDL fraction showed a CoQ10/chol ratio higher in NIDDM but not in IDDM patients, compared to controls. The CoQ10/triglycerides ratio was lower in NIDDM respect to controls and even lower in IDDM patients.

Topics: Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Biomarkers; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coenzymes; Female; Fructosamine; Humans; Lipoproteins; Male; Middle Aged; Reference Values; Risk Factors; Ubiquinone; Vitamin A; Vitamin E

Myeloperoxidase, a heme protein secreted by activated phagocytes, is present and enzymatically active in human atherosclerotic lesions. In the current studies, we explored the possibility that reactive nitrogen species generated by myeloperoxidase promote lipid peroxidation of low density lipoprotein (LDL) -- a modification that may render the lipoprotein atherogenic. We found that myeloperoxidase, an H2O2-generating system and nitrite (NO2-) peroxidized LDL lipids. The process required NO2- and each component of the enzymatic system; it was inhibited by catalase, cyanide and ascorbate, a potent scavenger of aqueous phase radicals. LDL peroxidation did not require chloride ion, and it was little affected by the hypochlorous acid scavenger taurine. Collectively, these results suggest that lipid peroxidation is promoted by a nitrogen dioxide radical-like species. These observations indicate that myeloperoxidase, by virtue of its ability to form reactive nitrogen intermediates, may promote lipid peroxidation and atherogenesis.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; Free Radicals; HL-60 Cells; Humans; Hydrogen Peroxide; Lipid Peroxidation; Lipoproteins, LDL; Nitrites; Nitrogen Dioxide; Peroxidase; Probucol; Vitamin E

Topics: Anticholesteremic Agents; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cholesterol, LDL; Diet; Europe; Folic Acid; Greece; Humans; Hyperhomocysteinemia; Lipoproteins; Pravastatin; Pyridoxine; Risk Factors; Societies, Medical; Triglycerides

L-Arginine, the physiologic substrate of nitric oxide synthase, has antiatherogenic properties in animal models of atherosclerosis, and improves endothelial function in hypercholesterolemic humans. Some of these effects may be mediated by increased production of nitric oxide; however, some investigators have postulated a direct antioxidant action related to its aminoguanidine moiety. We aimed therefore, to assess the antioxidant properties of L-arginine. The antioxidant properties of 200 microM L-arginine. 200 microM D-arginine and 200 microM L-glutamate were compared with the powerful antioxidant ascorbate and a control (phosphate-buffered saline). Compounds were tested using four in vitro methods: (1) the Esterbauer technique (which tests the ability of the compounds to scavenge free radicals or chelate transition metals); (2) the effect on the autoxidation of ascorbate; (3) anti-tocopherol mediated peroxidation (which tests the compound's ability to synergize with alpha-tocopherol to prevent mild chemically induced LDL oxidation); and (4) the ability of the compounds to attenuate alpha-tocopherol radical in micellular emulsions (TRAA). The above methods were repeated using the metabolites of the test compounds after incubation with human endothelial cells. Ex vivo studies were then carried out by measuring levels of lipid peroxide production (using HPLC with UV and chemiluminescence detection) in three healthy volunteers before and 2 h after a single 7-g oral dose of L-arginine. By the Esterbauer technique, L-arginine increased lag time by 45% compared to control, as did D-arginine by 50%; L-glutamate had no effect and ascorbate increased lag time by 325%. Neither L-arginine, D-arginine or L-glutamate had significant effects on the autoxidation of ascorbate or anti-tocopherol mediated peroxidation. By the TRAA method, L-arginine had a small effect on preventing the decay of tocopherol. The results were similar for the studies of the compound's metabolites. In ex vivo studies, no changes were seen in lipid peroxide levels following acute dosage with L-arginine. L-Arginine has only weak and non-specific antioxidant effects, suggesting that its major cardioprotective benefits occur through other mechanisms, such as via the nitric oxide pathway.

Topics: Adult; Antioxidants; Arginine; Arteriosclerosis; Ascorbic Acid; Chromatography, High Pressure Liquid; Free Radical Scavengers; Glutamic Acid; Humans; Lipid Peroxides; Lipoproteins, LDL; Male; Nitric Oxide; Oxidation-Reduction; Reference Values; Vitamin E

We have established a novel smooth muscle cell line (SVS) which retains the expression of specific markers for smooth muscle cells, such as smooth muscle myosin-1, calponin and SM22 alpha, from temperature-sensitive SV40 large T-antigen transgenic mice. SVS cells showed temperature-dependent growth and the expression of smooth muscle markers, showing that the differentiation stage can be controlled in this cell line by culture temperature. We have constructed luciferase-reporter cell lines for calponin and SM22 alpha genes by using SVS cells. We detected some compounds including ascorbic acid, which stimulated the expression of smooth muscle markers by the reporter assay. Ascorbic acid and its long lasting derivatives stimulated the expression of markers continuously. Moreover, ascorbic acid activated the expression of markers in synthetic SMCs seen in the intima of a rat balloon injury model. Thus, this reporter system should be useful for discovery of new antiatherosclerotic drugs.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Biomarkers; Calcium-Binding Proteins; Calponins; Cell Line; Mice; Mice, Transgenic; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Myosins

Exposure of plasma from apolipoprotein E gene knockout (apoE-/-) and control (CBA or C57BL/6J) mice plasma to a constant rate of aqueous peroxyl radicals (ROO.) resulted in the depletion of ascorbate, urate and alpha-tocopherol (alpha-TOH), with substantial and little lipid peroxidation, respectively. Alpha-TOH levels were 3-times higher in plasma from apoE-/- than control mice and its addition enhanced the oxidizability of control mouse plasma. In apoE-/- mouse plasma, alpha-TOH was associated primarily with very low density lipoprotein (VLDL), whereas in plasma from control mice, the vitamin was located largely in high density lipoproteins. Oxidation of isolated lipoproteins by ROO. resulted in the accumulation of lipid hydroperoxides to an extent that reflected the plasma concentration and alpha-TOH content of the different lipoprotein fractions. Oxidation of 'plasma' reconstituted from components of apoE-/- mice and/or human plasma showed that human and apoE-/- mouse lipoproteins peroxidized with similar kinetics, although the initiation of lipid peroxidation was greater in the presence of mouse than human lipoprotein-deficient plasma. Also, the chain length of lipid peroxidation in apoE-/- mouse plasma after ascorbate depletion appeared to be independent of the rate of ROO. generation. Together, these results show that the ROO. induced peroxidation of plasma lipoproteins in atherogenesis-susceptible apoE-/- mice exhibits some, though not all, features of tocopherol-mediated peroxidation (TMP). Therefore, apoE-/- mice may represent a suitable animal model to test a role for TMP in atherogenesis and the prevention of this disease by anti-TMP agents.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Ascorbic Acid; Cholesterol Esters; Humans; Kinetics; Lipid Peroxidation; Lipoproteins; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Peroxides; Uric Acid; Vitamin E

This study sought to investigate the relations between plasma antioxidant status, extent of atherosclerosis and activity of coronary artery disease.. Previous studies indicate that increased antioxidant intake is associated with decreased coronary disease risk, but the underlying mechanisms remain controversial.. Plasma samples were obtained from 149 patients undergoing cardiac catheterization (65 with stable angina, 84 with unstable angina or a myocardial infarction within 2 weeks). Twelve plasma antioxidant/oxidant markers were measured and correlated with the extent of atherosclerosis and the presence of an unstable coronary syndrome.. By multiple linear regression analysis, age (p < 0.001), diabetes mellitus (p < 0.001), male gender (p < 0.001) and hypercholesterolemia (p = 0.02) were independent predictors of the extent of atherosclerosis. No antioxidant/oxidant marker correlated with the extent of atherosclerosis. However, lower plasma ascorbic acid concentration predicted the presence of an unstable coronary syndrome by multiple logistic regression (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.40 to 0.89, p = 0.01). The severity of atherosclerosis also predicted the presence of an unstable coronary syndrome (OR 1.7, 95% CI 1.14 to 2.47, p = 0.008) when all patients were considered. When only patients with significant coronary disease were considered (at least one stenosis >50%), ascorbic acid concentration (OR 0.56, 95% CI 0.37 to 0.85, p = 0.008) and total plasma thiols (OR 0.52, 95% CI 0.34 to 0.80, p = 0.004) predicted the presence of an unstable coronary syndrome, whereas the extent of atherosclerosis did not.. These data are consistent with the hypothesis that the beneficial effects of antioxidants in coronary artery disease may result, in part, by an influence on lesion activity rather than a reduction in the overall extent of fixed disease.

Topics: Aged; Angina Pectoris; Angina, Unstable; Antioxidants; Arteriosclerosis; Ascorbic Acid; Biomarkers; Coronary Disease; Female; Humans; Linear Models; Lipid Peroxidation; Logistic Models; Male; Middle Aged; Myocardial Infarction

Antioxidant vitamins are hypothesized to help prevent atherosclerosis by blocking lipoprotein oxidation. We investigated the effects of dietary vitamins C and E on atherosclerosis in rabbits.. Forty New Zealand male rabbits were divided into 4 groups: 0.3% cholesterol diet with (LV) and without vitamin (LC), and 0.5% cholesterol diet with (HV) and without vitamins (HC). The treated groups consumed 137 +/- 8 mg/day vitamin C and 80 +/- 4 mg/day vitamin E for 10 weeks. Vitamin treatment did not significantly affect serum lipids. Alpha-tocopherol values were significantly higher in both serum (mg/dl) and omental fat (microg/g) among the treated rabbits (3.9 +/- 0.5 and 31.6 +/- 2.1 for LV, 1.7 +/- 0.2 and 12.1 +/- 1.9 for LC, 5.6 +/- 0.8 and 51.3 +/- 9.3 for HV and 1.9 +/- 0.3 and 8.2 +/- 0.4 for HC; p < 0.001). Vitamin treatment did not affect the percent of surface lesions in the aorta and pulmonary artery (23.8 +/- 5.2 and 20.1 +/- 3.3% for LV, 19.8 +/- 5.6 and 23.2 +/- 3.5% for LC, 28.1 +/- 6.5 and 51.1 +/- 4.2% for HV and 32.4 +/- 5.5 and 43.7 +/- 3.9% for HC, respectively; p = 0.981 and p = 0.562.. Although significantly higher values of alpha-tocopherol were found in both serum and omental fat, antioxidant vitamins C and E did not demonstrate a significant protective effect on atherosclerosis in lipid-fed rabbits during the 10-week study period.

Topics: Animals; Antioxidants; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Drug Combinations; Lipoproteins; Male; Oxidation-Reduction; Pulmonary Artery; Rabbits; Random Allocation; Triglycerides; Vitamin E

Several antioxidants inhibit atherosclerosis. This study investigated the hypothesis that combining vitamin E, a lipophilic antioxidant, with vitamin C, a hydrophilic antioxidant, and/or selenium, a cofactor of peroxidases that detoxify lipid peroxides, would inhibit atherosclerosis more effectively than vitamin E alone. We also considered whether regional variation in inhibition of atherosclerosis by antioxidants would be associated with regional variation in aortic lipophilic antioxidants. Rabbits were fed an atherogenic diet (control) or an atherogenic diet supplemented with vitamin E, vitamins E and C, vitamin E+selenium, vitamins E and C+selenium, or probucol (positive control). Supplements were as follows: vitamin E, 146 IU/d; vitamin C, 791 mg/d; selenium, 22 microg/d; or probucol, 406 mg/d. Vitamin C did not influence atherosclerosis. After 22 weeks of treatment, rank order of aortic atherosclerosis was control>vitamin E (with or without vitamin C)>vitamin E+selenium (with or without vitamin C)>probucol. Antioxidant treatment reduced aortic cholesterol concentrations 21% to 56%, 29% to 86%, and 19% to 75% for the aortic arch, descending thoracic aorta, and abdominal aorta, respectively (P<0.025 to P<0.0003 by ANOVA), with slightly greatly reductions for areas of atherosclerotic lesions. Some treatments reduced plasma cholesterol concentrations, but none altered the distribution of cholesterol among lipoproteins. Corrected for differences in plasma cholesterol concentrations, aortic cholesterol concentrations were reduced up to 72% (P<0.02) by the antioxidant treatments, with equal reductions by vitamin E+selenium and by probucol. Aortic alpha-tocopherol standardized by aortic cholesterol as a measure of aortic lipids was lower in the abdominal aorta than in the aortic arch of rabbits not given alpha-tocopherol and increased relatively more in the abdominal aorta than in the aortic arch with alpha-tocopherol supplementation. The results of this study suggest that vitamin E+ selenium inhibited atherosclerosis as effectively as an equally hypocholesterolemic dose of probucol by a mechanism(s) that is in part independent of effects on plasma and lipoprotein cholesterol concentrations. The tendency for greater efficacy of antioxidant treatments in the abdominal aorta than aortic arch may relate to the lower concentrations of alpha-tocopherol in the abdominal aorta of unsupplemented rabbits.

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Cholesterol; Diet, Atherogenic; Drug Therapy, Combination; Lipids; Lipoproteins; Probucol; Rabbits; Selenium; Vitamin E

Oxidized low density lipoprotein (LDL) promotes atherogenesis. Although pharmacological antioxidants such as probucol inhibit both LDL oxidation and atherosclerosis in hyperlipidemic animals, the effects of natural antioxidants such as vitamin E are inconclusive. To further determine the effects of supplemental dietary antioxidants in vivo, we evaluated whether combined dietary antioxidants (0.1% vitamin E, 0.5% beta-carotene, and 0.05% vitamin C) inhibit LDL oxidation and fatty streak lesion development in homozygous LDL receptor-null (LDLR-/-) mice fed a high-fat, high-cholesterol diet. An additional group of mice were fed black tea, which has been shown to inhibit LDL oxidation in vitro. After receiving a high-fat, high-cholesterol diet for 8 weeks, the combined antioxidant-supplemented (antioxidant) group (n=18), tea group (n=19), and control group (n=17) had equivalent plasma cholesterol levels. LDL oxidation, as measured by the lag phase of conjugated diene formation, was markedly inhibited in the antioxidant group compared with the tea or control groups [mean lag phases=143+/-7 (antioxidant), 100+/-5 (tea), and 84+/-4 (control) minutes; P<0.0001 antioxidant versus tea or control]. The cross-sectional surface area of fatty streak lesions in the aortic sinus was reduced by 60% in the antioxidant group compared with both the tea and control groups (P<0.0001 antioxidant versus tea or control). There was no difference in lesion area between tea and control groups. Although both LDL oxidation and atherosclerosis were significantly inhibited in the antioxidant group, no correlation between lag phase values and lesion size was observed among individual animals. Furthermore, black tea did not inhibit fatty streak development in LDLR-/- mice. These data suggest that combined natural dietary antioxidants inhibit both LDL oxidation and atherogenesis in animals with elevated LDL but that inhibition of LDL oxidation alone may not prevent the development of atherosclerosis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Cholesterol; Cholesterol, Dietary; Diet; Dietary Fats; Dietary Supplements; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Receptors, LDL; Tea; Triglycerides; Vitamin E

Accumulation of carbonyl derivatives of proteins (protein carbonyl) is taken as a biomarker of oxidative protein damage in aging and in various diseases. We detected protein carbonyls in situ in human diabetic arteriosclerotic tissues and characterized the formation of protein carbonyls. Protein carbonyls were identified in the thickened intima of arterial walls and co-localized with protein adducts formed by carbonyl amine chemistry between protein and carbonyl compounds derived from autoxidation of carbohydrates, lipids, and ascorbate, i.e. advanced glycation end products or glycoxidation products, such as carboxymethyllysine (CML) and pentosidine, and lipoxidation products, such as malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE). In vitro incubation of proteins with ascorbic acid accelerated the production of protein carbonyls as well as CML and pentosidine, and incubation with arachidonate accelerated the production of protein carbonyls as well as CML, MDA, and HNE. By contrast, incubation of proteins with glucose resulted in the production of CML and pentosidine, but not protein carbonyls. Schiff base inhibitors, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylace tanilide and aminoguanidine, inhibited the production of protein carbonyls after incubation with ascorbate and arachidonate. The present study suggests that ascorbate and polyunsaturated fatty acids, but not glucose, represent potential sources of protein carbonyls, and that both the glycoxidation and lipoxidation reactions contribute to protein carbonyl formation in aging and various diseases.

Topics: Arachidonic Acid; Arginine; Arteriosclerosis; Ascorbic Acid; Diabetic Angiopathies; Glucose; Glycation End Products, Advanced; Glycosylation; Humans; Lipid Peroxidation; Lipoproteins; Lysine; Malondialdehyde; Oxidation-Reduction; Oxidative Stress

Lipid peroxidation and LDL oxidation have been implicated in intimal hyperplasia and endothelial dysfunction following direct arterial trauma.. The aim of this study was to evaluate the effects of megadose of natural antioxidant vitamin E (VE) combined to vitamin C (VC) on the regenerated endothelial dysfunction.. A first group of rats (VE and C) (n = 10) was pretreated with VE (500 IU/kg/day) and VC (1200 mg/kg/day) for 4 weeks before aortic (thoracic) endothelial denudation with a Fogarty catheter. Rats were then fed with the same vitamin supplemented diet for 2 months. A second group (n = 10) was similarly denuded and treated with soya oil (SO), VE vehicle, for the same period; a third group (n = 10) was denuded only (DN); and a fourth group was maintained on a regular diet (CL) without denudation. Endothelial-dependent and independent relaxation was assessed in organ chambers.. Vascular relaxation to nitric oxide analogue sodium nitroprusside was not affected either by the regenerative process or the vitamin supplementation. However, endothelial-dependent relaxation to acetylcholine, was significantly preserved in VE and C (p < 0.01) treated animals compared to DN group.. These results suggest that, in this model, dietary megadose of antioxidants vitamin initiated 4 weeks before denudation can improve the post-regenerative endothelial dysfunction and could contribute to the prevention of the atherosclerotic process.

Topics: Acetylcholine; Animals; Antioxidants; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Catheterization; Cholesterol, LDL; Endothelium, Vascular; Hyperplasia; Lipid Peroxidation; Nitroprusside; Rats; Rats, Sprague-Dawley; Regeneration; Soybean Oil; Tunica Intima; Vasodilation; Vasodilator Agents; Vitamin E

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Coronary Disease; Humans; Neoplasms; Risk Factors; Treatment Outcome; Vitamin E

The Food and Drug Administration (FDA) is issuing an interim final rule to prohibit the use on foods of a claim relating to the relationship between antioxidant vitamins C and E and the risk in adults of atherosclerosis, coronary heart disease, certain cancers, and cataracts. This rule is in response to a notification of a health claim submitted under section 303 of the FDA Modernization Act of 1997 (FDAMA). FDA has reviewed statements that the petitioner submitted in that notification, and, in conformity with the requirements of FDAMA, the agency is prohibiting the claim because the statements submitted as the basis of the claim are not "authoritative statements" of a scientific body, as required by FDAMA; therefore, section 303 of FDAMA does not authorize use of this claim. As provided for in section 301 of FDAMA, this rule is effective immediately upon publication.

Topics: Adult; Arteriosclerosis; Ascorbic Acid; Cataract; Coronary Disease; Drug Approval; Food Labeling; Humans; Neoplasms; Risk Factors; United States; United States Food and Drug Administration; Vitamin E

The microcirculation was studied for 10 weeks in untreated rabbits (n = 12) and in rabbits treated with vitamin C in their drinking water (0.5 g/d; n = 6), a 1% cholesterol diet (n = 12), or a combination of the two treatments (n = 11). The studies were performed by direct intravital microscopic imaging of the conjunctiva of both eyes to evaluate blood flow velocity, microvessel diameter, and microhemorheologic conditions. As we reported previously, changes occurred in all of the aforementioned variables as a consequence of cholesterol feeding. After 3 and 6 weeks of feeding, there was a marked and significant (P < .0001) decrease in blood flow velocity in third-order arterioles, which was accompanied by stasis and erythrocyte aggregation in the smaller conjunctival vessels. When cholesterol treatment was combined with vitamin C, blood flow was almost identical to that of controls and significantly (P < .0001) higher than that of rabbits treated with cholesterol alone. All other changes were also significantly reduced by the addition of vitamin C treatment to the cholesterol diet. Cholesterol-treated rabbits developed macroscopic arterial lesions that were not significantly reduced by vitamin C treatment. Neither circulating oxysterol levels nor atheromas were reduced by vitamin C treatment, which also had no significant effect on lipid or circulating vitamin E levels. We have previously shown that the lipid-soluble antioxidant BHT is able to prevent both cholesterol-induced microcirculatory changes and the development of arterial lesions in rabbits. This phenomenon is compatible with a critical oxidation step occurring in the lipid phase that is common to both processes. The finding that microcirculatory changes can be prevented by a water-soluble antioxidant is compatible with a role for water-soluble oxidants in this context. The possibility is discussed that vitamin C might also be important for the microcirculation in humans.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Blood Flow Velocity; Blood Pressure; Cholesterol; Conjunctiva; Diet, Atherogenic; Erythrocyte Aggregation; Male; Microcirculation; Oxidation-Reduction; Rabbits

The present study was to investigate the levels of plasma lipid peroxide products including malondialdehyde (MDA) and conjugated dienes (CD), and antioxidants including enzyme superoxide dismutase, glutathione peroxidase, catalase, plasma vitamin E and vitamin C in diabetic patients. Fifty-eight diabetic subjects; 16 males and 42 females, aged 30-75 years, were recruited. Eighteen of them had diabetes and forty of them had diabetes with hyperlipidemia. Twenty-seven healthy subjects, 8 males and 19 females, aged 30-75 years, were used as the control group. The results showed that the concentrations of plasma MDA in diabetic patients with or without hyperlipidemia tended to be increased when compared to the controls but there were no significant differences. The CD values were increased significantly in both diabetic groups when compared with control subjects. Significantly elevated levels of plasma MDA and CD were found in diabetic patients with hypertriglyceridemia (> 150 mg%). This increment did not change the antioxidant status in both enzymes and vitamins except that the plasma vitamin E levels and the ratios of tocopherol: cholesterol were increased significantly. An increase of lipid peroxide in plasma may be one important factor in the development of vascular complication and atherosclerosis seen in diabetic patients.

Topics: Adult; Aged; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Catalase; Diabetes Mellitus; Female; Glutathione Peroxidase; Humans; Hyperlipidemias; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Superoxide Dismutase; Vitamin E

Oxidative modification of LDL by vascular cells has been proposed as a mechanism by which LDL becomes atherogenic. Antioxidants that can prevent LDL oxidation may therefore act as antiatherogens. We used endothelial cells (ECs) from human aortas (HAECs), human saphenous veins (HSECs), and bovine aortas (BAECs) to investigate the role of intracellular and extracellular vitamin C (ascorbate) in EC-mediated LDL modification. Incubation of LDL (0.1 mg protein per milliliter) with confluent HAECs in Ham's F-10 medium led to time-dependent modification of the lipoprotein. In contrast, incubation of LDL with HAECs in medium 199, which does not contain redox-active transition metal ions, did not lead to LDL modification. Both HAEC-mediated and cell-free LDL modifications in Ham's F-10 medium were strongly inhibited in a time- and dose-dependent manner by physiological concentrations of ascorbate. Confluent HAECs cultured under conventional conditions contained very little intracellular ascorbate (< 0.5 nmol/mg protein) but could be loaded with up to 20 nmol ascorbate per milligram protein in a time- and concentration-dependent manner. Ascorbate-loaded HAECs exhibited a lower capacity to modify LDL than did non-ascorbate-loaded control cells. When LDL was incubated with HSECs instead of HAECs, similar time- and concentration-dependent inhibitory effects on LDL modification of intracellular and extracellular ascorbate were observed. In contrast to human ECs, BAECs did not take up vitamin C and therefore only coincubation but not preincubation with ascorbate inhibited BAEC-mediated LDL modification. Our data show that enrichment of human vascular ECs with vitamin C lowers their capacity to modify LDL. In addition, extracellular vitamin C strongly inhibits EC-mediated, metal ion-dependent atherogenic modification of LDL.

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; beta Carotene; Cattle; Cholesterol, LDL; Coculture Techniques; Dose-Response Relationship, Drug; Endothelium, Vascular; Extracellular Space; Humans; Intracellular Membranes; Muscle, Smooth, Vascular; Oxidation-Reduction; Time Factors; Vitamin E

2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran (BO-653) is a novel antioxidant synthesized by theoretical designing based on the previous experimental findings and consideration. The antioxidant activities of BO-653 against the oxidative modification of low-density lipoprotein (LDL) induced by free radicals were studied. BO-653 was consumed faster than endogenous alpha-tocopherol and inhibited the formation of lipid hydroperoxides, which was observed during the consumption of alpha-tocopherol. Doxyl stearic acids incorporated into LDL as spin probes competed with the antioxidants in scavenging radicals. It was found that the efficacy of radical scavenging by alpha-tocopherol became smaller as the radical went deeper into the interior of LDL particle, whereas that by BO-653 did not change. Ascorbic acid in the aqueous phase spared alpha-tocopherol efficiently during oxidation. On the other hand, the sparing effect of ascorbic acid for BO-653 was not remarkable, unlike that for alpha-tocopherol, which implied different locations of radicals derived from BO-653 and alpha-tocopherol within the LDL particle. It was concluded that BO-653 protected LDL from oxidative modification efficiently by scavenging peroxyl radicals and by reducing alpha-tocopheroxyl radicals and that this novel antioxidant might act as a potent inhibitor of development of atherosclerosis.

Topics: Amidines; Animals; Antioxidants; Apolipoproteins B; Arteriosclerosis; Ascorbic Acid; Azo Compounds; Benzofurans; Cyclic N-Oxides; Drug Design; Free Radical Scavengers; Humans; Kinetics; Lipid Peroxidation; Lipid Peroxides; Lipoproteins, LDL; Nitriles; Oxidants; Oxidation-Reduction; Peroxides; Rabbits; Vitamin E

Oxysterols as oxidation products of cholesterol are considered an atherogenic factor in the development of atherosclerosis in the arteries of cholesterol-fed rabbits. We compared the atherogenic effects of diets enriched either with 0.5% oxidized cholesterol (OC; characterized by high amounts of oxysterols) or with pure cholesterol (PC). The effects of antioxidant vitamins E and C added to the PC diet were also evaluated in view of their antioxidative properties for lipoproteins and cholesterol and how this could affect the severity of atherosclerosis. Four groups of rabbits were fed the following for 11 wk: 1) a nonpurified stock diet, 2) this stock diet plus 0.5% OC, 3) the stock diet plus 0.5% PC, and 4) the stock diet plus 0.5% PC and 1000 mg vitamin E and 500 mg vitamin C/kg diet (PC + antioxidants). The OC and PC diets were equally hyperlipidemic and hypercholesterolemic. The severity of atherosclerotic lesions was highest with the OC diet and lowest with the PC + antioxidants diet. The plasma oxysterol concentration was proportional to the severity of atherosclerosis in all three groups of cholesterol-fed rabbits. beta-Very-low-density-lipoprotein modification was minimized by vitamins E and C as indicated by its polyacrylamide gel electrophoretic pattern and its increased binding to the rabbit liver membrane in vitro. This study indicated that OC and PC were equally atherogenic but that the addition of antioxidants to the PC diet significantly reduced its severity, even when hypercholesterolemia persisted. This indicated that atherogenesis can result from an excessive accumulation of oxidation products of cholesterol in the plasma.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cholesterol, Dietary; Diet, Atherogenic; Hypercholesterolemia; Lipid Peroxidation; Lipoproteins, VLDL; Liver; Male; Rabbits; Severity of Illness Index; Vitamin E

It has been suggested that iron plays an important role in the pathogenesis of atherosclerosis, primarily by acting as a catalyst for the atherogenic modification of LDL. Although some epidemiological data suggest that high stored iron levels are an independent risk factor for coronary artery disease and that iron has been detected in both early and advanced atherosclerotic lesions, the evidence is often contradictory and inconclusive. We used the New Zealand White rabbit to investigate the effects of iron overload (FeO) and iron deficiency (FeD) on atherosclerosis. Groups of 7 rabbits were either iron loaded by injections of iron dextran (FeO group), iron depleted by phlebotomy (FeD group), or given injections of saline (control group) for a total of 9 weeks. All rabbits were fed a chow diet containing 1% (wt/wt) cholesterol for the last 6 weeks of the study. Iron and antioxidant status and cholesterol levels were assayed in plasma before cholesterol feeding (week 3) and at the time that the rabbits were killed (week 9). In addition, the susceptibility of LDL to oxidation was measured and pathological examination of the aortic arch and thoracic aorta performed at the end of the study. FeD significantly decreased the levels of blood hemoglobin, serum iron, and transferrin saturation compared with controls. Conversely, FeO significantly increased transferrin Fe saturation. FeO but not FeD decreased plasma cholesterol levels compared with control animals both before (P < .05) and after (P = .055) cholesterol feeding. Neither FeO nor FeD had a significant effect on the levels of antioxidants and lipid peroxidation products in plasma and aortic tissue or on the susceptibility of LDL to ex-vivo oxidation. FeO significantly decreased aortic arch lesion formation by 56% compared with controls (P < .05), whereas FeD had no significant effect. These results indicate that in this animal model, FeO decreases rather than increases atherosclerosis, likely because iron dextran exerts a hypocholesterolemic effect. Our data do not support the hypotheses that elevation of Fe stores increases or that a reduction of Fe stores by phlebotomy decreases the risk of coronary artery disease.

Topics: Animals; Antioxidants; Aorta; Aortic Diseases; Arteriosclerosis; Ascorbic Acid; Diet, Atherogenic; Hypercholesterolemia; Iron; Iron Deficiencies; Iron Overload; Lipid Peroxidation; Lipids; Lipoproteins, LDL; Male; Phlebotomy; Prostaglandins F; Rabbits; Risk Factors; Vitamin E

In order to study the inhibitory effects of antioxidant vitamins on serum (low oxidative density lipoproteins, oxLDL) and experimental atherosclerosis in rabbits, 20 rabbits were fed on cholesterol rich diet and antioxidant vitamins (vitamin E, vitamin C and beta carotene) for 12 weeks. oxLDL were tested by ELISA at the beginning of experiment and after 4 weeks 8 weeks.. The results showed that supplement of antioxidant vitamins can decrease the oxLDL level significantly and inhibited development of atherosclerosis lesion around aorta in rabbits.

Topics: Animals; Antioxidants; Aorta; Arteriosclerosis; Ascorbic Acid; beta Carotene; Lipoproteins, LDL; Male; Rabbits; Vitamin E

To explore pathophysiological mechanisms of cigarette smoking involved in atherogenesis, we compared adhesiveness of isolated blood monocytes with endothelium and plasma levels of the aqueous phase antioxidant vitamin C in nonsmokers and smokers before and after supplementation, using a novel monocyte adhesion assay with fixed human endothelial cells.. Monocyte adhesion to unstimulated human umbilical vein endothelial cells ranged from 0.17% to 0.51% in the nonsmoker group (0.37+/-0.09%, mean +/-SD, n=13). In smokers with a 1 to 2 packs per day consumption, monocyte adhesion was increased to 0.71+/-0.17% (mean +/-SD, n=10, P<.001), ranging from 0.46% to 0.99%. Increased adhesiveness was mediated by the integrin CD11b/CD18, as shown by inhibition with a monoclonal antibody to CD11b but not associated with altered CD11b surface expression. Plasma vitamin C levels were reduced in smokers (48.2+/-14.1 micromol/L) versus nonsmokers (67.7+/-17.6 micromol/L; P<.025), while no significant differences were found in retinol, vitamin E, or beta-carotene levels. This confirms that the radical scavenger vitamin C reacts sensitively to oxidative stress induced by cigarette smoke in human plasma. Consistently, dietary supplementation with vitamin C (2 g per day) for 10 days raised plasma levels to 82.6+/-11.0 micromol/L (n=10, P<.001) in smokers and decreased monocyte adhesion to values found in nonsmokers (0.38+/-0.18%, P<.001). In contrast, vitamin C intake did not affect monocyte adhesiveness in nonsmokers (0.37+/-0.14%, n=6) despite increasing plasma levels to 82.9+/-11.8 micromol/L.. Our data show that cigarette smoking increases CD11b-dependent monocyte adhesiveness in humans. Restoring reduced plasma vitamin C concentrations in smokers by oral supplementation decreased monocyte adhesion to values found in nonsmokers.

Topics: Adult; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cell Adhesion; Cells, Cultured; Diet; Endothelium, Vascular; Humans; Male; Monocytes; Nicotiana; Plants, Toxic; Smoking

Oxidative modification of LDL is thought to be a radical-mediated process involving lipid peroxides. The small dense LDL subpopulations are particularly susceptible to oxidation, and individuals with high proportions of dense LDL are at a greater risk for atherosclerosis. An oxidatively modified plasma LDL, referred to as LDL-, is found largely among the dense LDL fractions. LDL- and dense LDL particles also contain much greater amounts of lipid peroxides compared with total LDL or the more buoyant LDL fractions. The content of LDL- in dense LDL particles appears to be related to copper- or heme-induced oxidative susceptibility, which may be attributable to peroxide levels. The rate of lipid peroxidation during the antioxidant-protected phase (lag period) and the length of the antioxidant-protected phase (lag time) are correlated with the LDL- content of total LDL. Once LDL oxidation enters the propagation phase, there is no relationship to the initial LDL- content or total LDL lipid peroxide or vitamin E levels. Beyond a threshold LDL- content of approximately 2%, there is a significant increase in the oxidative susceptibility of nLDL particles (ie, purified LDL that is free of LDL-), and this susceptibility becomes more pronounced as the LDL- content increases. nLDL is resistant to copper- or heme-induced oxidation. The oxidative susceptibility is not influenced by vitamin E content in LDL but is strongly inhibited by ascorbic acid in the medium. Involvement of LDL(-)-associated peroxides during the stimulated oxidation of LDL is suggested by the inhibition of nLDL oxidation when LDL- is treated with ebselen prior to its addition to nLDL. Populations of LDL enriched with LDL- appear to contain peroxides at levels approaching the threshold required for progressive radical propagation reactions. We postulate that elevated LDL- may constitute a pro-oxidant state that facilitates oxidative reactions in vascular components.

Topics: Adult; Antioxidants; Arteriosclerosis; Ascorbic Acid; Centrifugation, Density Gradient; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Humans; Lipid Peroxidation; Lipoproteins, LDL; Oxidation-Reduction; Risk Factors; Vitamin E

Consumption of a range of dietary antioxidants may be beneficial in protecting low density lipoprotein (LDL) against oxidative modification, as studies have demonstrated that antioxidants other than vitamin E may also function against oxidation of LDL in vitro. In the present study, the effect of polyphenol antioxidants on the susceptibility of LDL to copper-mediated oxidation was investigated after feeding semi-purified diets to 3 groups of New Zealand white (NZW) rabbits. All diets comprised 40% energy as fat with 17% energy as oleic acid. Dietary fatty acid compositions were identical. Oils with different polyphenol contents were used to provide the dietary source of oleic acid-refined olive oil, extra virgin olive oil and Trisun high oleic sunflower seed oil. Polyphenolic compounds (hydroxytyrosol and p-tyrosol) could only be detected in the extra virgin olive oil. Vitamin E was equalised in all diets. LDL oxidizability in vitro was determined by continuously monitoring the copper-induced formation of conjugated dienes after 6 weeks of experimental diet feeding. The lag phase before demonstrable oxidation occurred was significantly increased in the high polyphenol, extra virgin olive oil group (P < 0.05) when compared with combined results from the low polyphenol group (refined olive oil and Trisun), even though the LDL vitamin E concentration in the high polyphenol group was significantly lower. The rate of conjugated diene formation was not influenced by the presence of dietary polyphenols. Results demonstrate that antioxidants, possibly phenolic compounds which are present only in extra virgin olive oil, may contribute to the endogenous antioxidant capacity of LDL, resulting in an increased resistance to oxidation as determined in vitro.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Coconut Oil; Dietary Fats, Unsaturated; Disease Susceptibility; Energy Intake; Fatty Acids; Female; Flavonoids; Food Handling; Lipid Peroxidation; Lipoproteins, LDL; Malondialdehyde; Olive Oil; Oxidation-Reduction; Phenols; Plant Oils; Polymers; Polyphenols; Rabbits; Risk Factors; Sunflower Oil; Uric Acid; Vitamin E

Latent scurvy is characterized by a reversible atherosclerosis that closely resembles the clinical form of this disease. Acute scurvy is characterized by microvascular complications such as widespread capillary hemorrhaging. Vitamin C (ascorbate) is required for the synthesis of collagen, the protein most critical in the maintenance of vascular integrity. We suggest that in latent scurvy, large blood vessels use modified LDL--in particular lipoprotein(a)--in addition to collagen to maintain macrovascular integrity. By this mechanism, collagen is spared for the maintenance of capillaries, the sites of gas and nutrient exchange. The foam-cell phenotype of atherosclerosis is identified as a mesenchymal genetic program, regulated by the availability of ascorbate. When vitamin C is limited, foam cells develop and induce oxidative modification of LDL, thereby stabilizing large blood vessels via the deposition of LDL. The structural similarity between vitamin C and glucose suggests that hyperglycemia will inhibit cellular uptake of ascorbate, inducing local vitamin C deficiency.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Collagen; Diabetes Complications; Diabetes Mellitus; Foam Cells; Humans; Hyperglycemia; Lipoprotein(a); Metaplasia; Models, Biological; Scurvy

The relationship between serum ascorbic acid (AA) and diabetic macroangiopathy was studied. Fifty-six patients with noninsulin-dependent diabetes mellitus were examined, together with 20 healthy controls matched for age against the diabetes patients. Aortic pulse wave velocity (PWV) was taken as an index of the severity of atherosclerosis. The level of serum AA in diabetic patients was significantly lower than that of the controls. Among the diabetic groups, those with elevated PWV levels by age demonstrated a significant drop in AA. No significant differences were seen in the level of serum dehydroascorbic acid (DHAA) between patients and controls, nor were there any significant differences among patient groups. The concentration of serum AA was inversely related to the risk factors of atherosclerosis, such as body mass index, Apo B/ Apo A-I ratio, thiobarbituric acid-reactive substances (TBARS), and microalbumin in urine. It was inferred from these findings that the depletion of serum AA was apparent in diabetics with advanced atherosclerosis.

Topics: Adult; Aged; Albuminuria; Aorta; Apolipoprotein A-I; Apolipoproteins B; Arteriosclerosis; Ascorbic Acid; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Male; Middle Aged; Rheology; Thiobarbituric Acid Reactive Substances

Atherosclerosis is a common problem among the elderly. Because lipid peroxidation is considered a contributor to the development of atherosclerosis, we compared oxidative properties of lipoproteins in an otherwise healthy (SENIEUR-classified) aged population (65-74 years) with young controls (18-30 years). Relative amounts of oxidatively altered low density lipoprotein (LDL), estimated by means of an antibody against LDL modified by 4-hydroxynonenal, a product of lipid peroxidation, were increased marginally in serum from the elderly (9.8 vs. 7.4%, P = 0.07). In contrast, isolated LDL from the elderly revealed a decreased susceptibility to in vitro oxidation: the lag time was increased (2.34 vs. 2.10 h, P < 0.01), and the maximal rate of LDL oxidation decreased (0.88 vs. 1.01 O.D./h, P = 0.001). However, there were no age-related changes in lipid composition of native LDL and consumption of fatty acids during in vitro oxidation. The serum concentrations of ascorbic acid and most lipophilic anti-oxidants (the latter expressed per g serum lipids) were significantly decreased in the elderly except tocopherols which tended to be higher. In conclusion, our data reveal paradox age-related alterations of LDL as to its behaviour in oxidation in vivo vs. in vitro.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Aldehydes; Antioxidants; Arteriosclerosis; Ascorbic Acid; Fatty Acids; Female; Humans; Lipid Peroxidation; Lipoproteins, LDL; Male; Oxidation-Reduction; Thiobarbituric Acid Reactive Substances; Vitamins

Whilst catalytic iron has been implicated in the development of atherosclerosis by initiating low density lipoprotein (LDL) oxidation, the source of such iron remains uncertain. Here, we show that LDL oxidation in the presence of ferritin was stimulated by ascorbate (15-60 microM), whilst this effect was inhibited by the iron chelator desferrioxamine. Ascorbate also showed an antioxidant activity at high concentrations (125-250 microM). Our results suggest that the combination of ascorbate with ferritin may supply free iron for LDL oxidation in vivo.

Topics: Arteriosclerosis; Ascorbic Acid; Chelating Agents; Deferoxamine; Ferritins; Iron; Kinetics; Lipid Peroxidation; Lipoproteins, LDL

We examined the interactive effect of oxidized low density lipoprotein (LDL) and ascorbic acid on collagen production in cultured smooth muscle cells (SMCs). Porcine aortic SMCs were incubated with 50-200 micrograms/ml of human LDL with/without 5 microM Cu2+ for 24 h. Collagen production was assayed by successive salt precipitation at acidic and neutral pH after pepsin digestion of 3H-proline-labeled collagenous protein. Oxidation of LDL was evaluated by electrophoresis and by the level of thiobarbituric acid reactive substances (TBARS). Ascorbic acid reduced the oxidation of LDL + Cu2+ (53% reduction). In the presence of ascorbic acid, no differences were noted in collagen production between LDL and LDL + Cu2+. Without ascorbic acid, collagen production with LDL + Cu2+ was increased dose-dependently up to 6-fold with 150 micrograms/ml LDL, while no such effects were observed at any doses of native LDL. The addition of butylated hydroxytoluene to LDL + Cu2+ strongly suppressed oxidation (88% reduction), and significantly reduced collagen production close to that seen with native LDL. These results indicate that oxidized LDL stimulates collagen production in SMCs, while native LDL does not. Therefore, oxidized LDL may play a direct role in stimulating collagen production in SMCs, which could lead to collagenosis in atherosclerosis.

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Butylated Hydroxytoluene; Cells, Cultured; Collagen; Copper; DNA Replication; Gene Expression Regulation; Humans; Lipid Peroxidation; Lipoproteins, LDL; Muscle, Smooth, Vascular; Oxidation-Reduction; Platelet-Derived Growth Factor; Serum Albumin, Bovine; Swine; Thiobarbituric Acid Reactive Substances

Evidence that dietary antioxidants may prevent atherosclerotic disease is growing. The relationship between the intake of dietary and supplemental vitamin C, alpha-tocopherol, and provitamin A carotenoids and average carotid artery wall thickness was studied in 6318 female and 4989 male participants 45 to 64 years old int he Atherosclerosis Risk in Communities Study.. Intake was assessed by use of a 66-item semiquantitative food-frequency questionnaire. Carotid artery intima-media wall thickness was measured as an indicator of atherosclerosis at multiple sites with B-mode ultrasound. Among men and women > 55 years old who had not recently begun a special diet, there was a significant inverse relationship between vitamin C intake and average artery wall thickness adjusted for age, body mass index, fasting serum glucose, systolic and diastolic blood pressures, HDL and LDL cholesterol, total caloric intake, cigarette use, race, and education (test for linear trend across quintiles of intake, P = .019 for women and P = .035 for men). An inverse relationship was also seen between wall thickness and alpha-tocopherol intake but was significant only in women (test for linear trend, P = .033 for women and P = .13 for men). There was a significant inverse association between carotene intake and wall thickness in older men (test for linear trend, P = .015), but the association weakened after adjustment for potential confounders. No significant relationships were seen in participants < 55 years old.. These data provide limited support for the hypothesis that dietary vitamin C and alpha-tocopherol may protect against atherosclerotic disease, especially in individuals > 55 years old.

Topics: Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Carotenoids; Carotid Arteries; Diet; Energy Intake; Female; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Prospective Studies; Risk Factors; Ultrasonography; United States; Vitamin E

We assessed the antioxidant status and contents of unoxidized and oxidized lipids in freshly obtained, homogenized samples of both normal human iliac arteries and carotid and femoral atherosclerotic plaque. Optimal sample preparation involved homogenization of human atherosclerotic plaque for 5 minutes, which resulted in recovery of most of the unoxidized and oxidized lipids without substantial destruction of endogenous vitamins C and E and 87% and 43% recoveries of added standards of alpha-tocotrienol and isoascorbate, respectively. The total protein, lipid, and antioxidant levels obtained from human plaque varied among donors, although the reproducibility of replicates from a single sample was within 3%, except for ubiquinone-10 and ascorbate, which varied by 20% and 25%, respectively. Plaque samples contained significantly more ascorbate and urate than control arteries, with no discernible difference in the vitamin C redox status between plaque and control materials. The concentrations of alpha-tocopherol and ubiquinone-10 were comparable in plaque samples and control arteries. However, approximately 9 mol percent of plaque alpha-tocopherol was present as alpha-tocopherylquinone, whereas this oxidation product of vitamin E was not detectable in control arteries. Coenzyme Q10 in plaque and control arteries was only detected in the oxidized form ubiquinone-10, although coenzyme Q10 oxidation may have occurred during processing. The most abundant of all studied lipids in plaque samples was free cholesterol, followed by cholesteryl oleate and cholesteryl linoleate (Ch18:2). Approximately 30% of plaque Ch18:2 was oxidized, with 17%, 12%, and 1% present as fatty acyl hydroxides, ketones, and hydroperoxides, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antioxidants; Arteries; Arteriosclerosis; Ascorbic Acid; Humans; Lipid Metabolism; Lipid Peroxidation; Lipids; Middle Aged; Oxidation-Reduction; Vitamin E

An imbalance between pro-oxidants and antioxidants is operative in atherosclerosis. Cigarette smoke is a major risk factor of atherosclerosis and has been reported to contain large amounts of oxidants. We assessed arterial (internal mammary artery) and plasma levels of vitamins E and C and lipid peroxides in 48 male patients, 24 smokers and 24 non-smokers, undergoing coronary bypass surgery. Lipid peroxidation was studied using fluorescent products of lipid peroxidation (FPLs). Tissue vitamins E and C levels were significantly lower and FPLs significantly higher in smokers than in non-smokers (P < 0.0006, 0.0005 and 0.0005, respectively). This pattern was associated with lower vitamin C and higher lipid peroxide plasma levels in smokers than in non-smokers (P < 0.0002 and 0.0005, respectively). Vitamins E and C plasma levels were strongly related to their tissue content both in smokers (r = 0.60, P < 0.005 and r = 0.57, P < 0.01) and in non-smokers (r = 0.42, P < 0.05 and r = 0.46, P < 0.05). Moreover, vitamin E content was significantly related to that of vitamin C only in the arterial tissue of both groups, pointing to the existence of a functional interaction between these antioxidants. In both groups, FPLs were significantly and inversely related to vitamin C in plasma and to vitamin E in tissue, suggesting the antioxidant primary of vitamin C and vitamin E in the plasma and arterial tissue compartments, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arteries; Arteriosclerosis; Ascorbic Acid; Case-Control Studies; Humans; Lipid Peroxidation; Male; Middle Aged; Smoking; Vitamin E

Topics: Anticholesteremic Agents; Arteriosclerosis; Ascorbic Acid; Clinical Trials as Topic; Coronary Disease; Female; Humans; Hypercholesterolemia; Lipoproteins, LDL; Male; Meta-Analysis as Topic; Risk Factors

The effects of administration of guava and papaya fruit (100 g/day), vegetables, and mustard oil (5 g/day) (group A); antioxidant vitamins C (50 mg/day) and E (30 mg/day), plus betacarotene (10 mg/day) (group B); a high-fat (5-10 g/day) (group C); or a low-fat (4-5 g/day) diet (group D) were compared over 24 diet weeks in a randomized fashion, while all groups of rabbits (five in each of four groups) received a hydrogenated fat diet (5-10 g/day) for a period of 36 weeks. After 12 weeks on the high-fat diet, each group of rabbits had an increase in blood lipoproteins. The fruit and vegetable-enriched prudent diet (group A) caused a significant decline in blood lipids at 24 and 36 weeks, whereas the lipid levels increased significantly in groups C and D. Group A also had a significant rise in vitamin E (2.1 Umol/l), C (10.5 Umol/l), A (0.66 Umol/l), and carotene (0.08 Umol/l) and a decrease in lipid peroxides (0.34 nmol/ml at 36 weeks, whereas the levels were unchanged in groups C and D. Group B rabbits had a significant and greater increase than group A in plasma vitamins E, C, A, and carotene; a rise in HDL cholesterol; and a greater decrease in lipid peroxides after 24 and 36 weeks of treatment. After stimulation of lipid peroxidation in all rabbits, 3 of 5 group C and 2 of 5 group D rabbits died due to coronary thrombosis, whereas in groups A and B there were no deaths, indicating that antioxidant therapy can provide protection against lipid peroxidation and free radical generation. Aortic lipids and sudanophilia, indicating atherosclerosis, were significantly higher in groups C and D than in groups A and B. Fatty streaks and atheromatous and fibrous plaques were noted in all the rabbits in groups C and D. Intimal fibrosis and medial degeneration were also present in the group C rabbits. While group A (36.4 +/- 4.4 microns) and group B (37.1 +/- 4.2 microns) rabbits had minimal coronary artery plaque sizes, group C (75.4 +/- 10.6 microns) and group D rabbits (69.5 +/- 6.2 microns) had significantly greater plaque sizes. Aortic plaque sizes were also greater in groups C and D than in groups A and B. It is possible that combined therapy with antioxidant vitamins C, E, and carotene, and a diet rich in antioxidants, could independently inhibit free radical generation and the development of atherosclerosis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; beta Carotene; Dietary Fats; Hyperlipidemias; Lipid Peroxidation; Oxidative Stress; Rabbits; Vitamin E

Selected parameters of lipid metabolism (cholesterol, HDL cholesterol, LDL cholesterol, atherogenic index, triacylglycerols, vitamin C, vitamin E, vitamin E/cholesterol, plasma fatty acid profile) and pro-oxidative/anti-oxidative parameters (conjugated dienes of fatty acids, activity of catalase and glutathione peroxidase) were estimated in blood of 59 healthy vegetarians aged 19-30 years. When compared to non-vegetarians, no incidence of obesity, low levels of cholesterol, LDL cholesterol, atherogenic index or triacylglycerols, HDL cholesterol levels on the margin of 1.4 mmol/l (boundary level between standard and reduced risk) as well as a higher plasma content of polyunsaturated fatty acids and a higher 18:2/18:1 ratio were all favourable consequences of vegetarianism with respect to atherosclerosis prevention. These factors are completed by higher levels of protective compounds with antisclerotic activity (vitamin C, vitamin E/cholesterol--protecting LDL from lipoperoxidation) as well as by beneficial pro-oxidative/anti-oxidative parameters (low values of conjugated dienes, significantly higher activity of catalase, higher level of vitamin C).

Topics: Adult; Aging; Arteriosclerosis; Ascorbic Acid; Body Mass Index; Catalase; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diet, Vegetarian; Fatty Acids; Female; Glutathione Peroxidase; Humans; Lipid Metabolism; Lipids; Male; Triglycerides; Vitamin E

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Disease Models, Animal; Endothelium, Vascular; Homocysteine; Homocystinuria; Humans; Male; Microscopy, Electron, Scanning; Perfusion; Rats; Rats, Sprague-Dawley

Hypertension is associated with an increased risk of atherosclerosis. Free radical oxidative damage has been implicated in the atherogenic process. We measured levels of the antioxidants uric acid, thiols, vitamins C, A and E as well as the total antioxidant capacity in 21 normotensive controls, 22 patients whose hypertension was controlled on drugs and 30 patients with uncontrolled hypertension. Mean BPs in the groups were 125/76, 132/80 and 181/98 mmHg, respectively. When compared with controls, both hypertensive groups had significantly lower serum ascorbic acid (54 +/- 5 vs. 37 +/- 6 vs. 38 +/- 5 mumol/l, P < 0.05) and albumin-corrected thiol levels (9.91 +/- 0.18 vs. 8.69 +/- 0.20 vs. 8.92 +/- 0.19 mumol/g, P < 0.05). The levels of the other antioxidants did not differ significantly between the groups. Levels of von Willebrand factor, a marker of endothelial damage, were correlated with SBP but not with antioxidant status. We conclude that hypertensive subjects have lower levels of the antioxidants vitamin C and thiols and this may reflect greater oxidative consumption. The implications for atherogenesis and endothelial function and integrity in hypertension are discussed.

Topics: Adult; Aged; Analysis of Variance; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Ascorbic Acid; Biomarkers; Endothelium, Vascular; Female; Free Radical Scavengers; Humans; Hypertension; Male; Middle Aged; Uric Acid; Vitamin A; Vitamin E; von Willebrand Factor

Topics: Arteriosclerosis; Ascorbic Acid; Humans; Vitamin A; Vitamin E

New Zealand White rabbits were made hypercholesterolemic by feeding a high cholesterol diet (10 g/kg diet) with or without added antioxidants. The antioxidants used were either probucol (10 g/kg) or vitamin E (10 g/kg) plus vitamin C (0.6 g/kg). Serum cholesterol concentrations were monitored as a function of time. At the end of 10 wk, serum and lipoprotein vitamin E concentrations, the extent of oxidation of lipoprotein fractions (thiobarbituric acid reacting substances), the susceptibility of lipoprotein to oxidation in vitro (conjugated diene formation) and the extent of atherosclerosis (aortic area stained by Sudan IV and plaque thickness) were measured. Rabbits fed diets supplemented with vitamins E and C had markedly higher serum vitamin E concentrations, marked vitamin E enrichment in all lipoprotein fractions, less oxidation in VLDL and LDL and enhanced resistance of LDL to further in vitro oxidation, but did not have significantly less aortic atherosclerosis. Rabbits given supplemental probucol likewise exhibited reduced oxidation of lipoproteins. However, aortic atherosclerosis in these animals was significantly lower, as were serum cholesterol concentrations. Inhibition of lipoprotein oxidation itself was not sufficient to reduce atherosclerosis in cholesterol-fed New Zealand White rabbits.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cholesterol, Dietary; Drug Interactions; Lipoproteins; Oxidation-Reduction; Probucol; Rabbits; Vitamin E

The oxidative modification of low density lipoprotein (LDL) has been proposed as an important causative event in the development of human atherosclerosis. As a corollary of this hypothesis, antioxidants that can prevent LDL oxidation may inhibit atherosclerosis. Oxidative modification of LDL in vitro, either induced by Cu2+ or mediated by cultured arterial wall cells in media containing trace amounts of transition metal ions, is strongly inhibited by vitamin C (L-ascorbic acid (AA)). AA, however, is known to act as a prooxidant rather than an antioxidant in the presence of transition metal ions. We observed that AA is oxidized rapidly when incubated with Cu2+ and LDL, leading to transient formation of dehydro-L-ascorbic acid (DHA). Although AA and DHA can no longer be detected after 3.5 h of incubation, LDL resists oxidative modification for at least 20 h, as assessed by anodic gel electrophoretic mobility. Remarkably, DHA protects LDL more effectively against both Cu(2+)-induced lipid peroxidation and shifts in electrophoretic mobility than does AA; indeed, AA per se, without oxidation to DHA, offers no protection. By inhibiting oxidative modification of LDL, AA and DHA prevent uptake of LDL by macrophages via the scavenger receptor pathway. When LDL is incubated with DHA followed by gel filtration, LDL remains protected against subsequent Cu(2+)-induced oxidative modification, suggestive of stable modification of LDL in the presence of DHA. In contrast, DHA is ineffective against a metal ion-independent type of oxidative stress, viz. aqueous peroxyl radicals; under these conditions, only AA is able to inhibit lipid peroxidation in LDL. Our data indicate that vitamin C protects LDL against atherogenic modification by two different mechanisms that may act in concert: (i) free radical scavenging by AA prevents aqueous oxidants from attacking and oxidizing LDL, and (ii) stable modification of LDL by DHA or decomposition product(s) thereof imparts increased resistance to metal ion-dependent oxidation.

Topics: Adult; Arteriosclerosis; Ascorbic Acid; Copper; Dehydroascorbic Acid; Female; Free Radical Scavengers; Free Radicals; Humans; Lipid Peroxidation; Lipoproteins, LDL; Macrophages; Male; Oxidation-Reduction; Pentetic Acid; Peroxides

Oxidative modification of LDL may represent an initiating event in the formation of monocyte-macrophage foam cells, a major cell present in fatty streaks and atherosclerotic fibrous plaques. Therefore, we studied the effect of such antioxidants as probucol (500 mg/kg) and vitamins E and C (500 mg/kg each) on the regression of induced iliac-femoral lesions and progression of naturally occurring thoracic aortic fatty streak lesions in hypercholesterolemic New Zealand White rabbits. Following an initial 9-week lesion induction phase, both therapies were evaluated for 8 weeks. Probucol lowered plasma cholesterol 47% while vitamins E and C had no effect on plasma cholesterol. Probucol decreased the cholesteryl ester (CE) content of the thoracic aorta by 31% without changing the thoracic aortic lesion coverage. Vitamins E and C decreased thoracic aortic CE content by 40% and lesion coverage by 46%. Neither probucol nor vitamins E and C altered the CE content, lesion size, or macrophage/lesion ratio of the iliac-femoral artery. Thus, we conclude that the effects of antioxidants are specific to the stage of atherosclerotic lesion development. Antioxidant therapy alters the progression and cholesteryl ester enrichment of diet-induced thoracic aortic fatty streaks but has no effect on the progression and/or regression of more complicated injury-induced iliac-femoral lesions.

Topics: Animals; Antioxidants; Aorta; Arteriosclerosis; Ascorbic Acid; Blood Vessels; Cholesterol; Cholesterol Esters; Femoral Artery; Hypercholesterolemia; Lipids; Lipoproteins; Male; Probucol; Rabbits; Vitamin E

The exposure of mouse peritoneal macrophages to cholesterol linoleate-containing artificial lipoproteins can lead to intracellular ceroid accumulation. This can be used as a model to study the role of oxidation in macrophage uptake of lipoproteins containing unsaturated fatty acids, considered by many as a primary event in atherosclerotic plaque formation. Our studies show that ascorbic acid can both inhibit and promote the formation of ceroid in such a model system. The transition metal copper (Cu(II)) further elevates ceroid accumulation and EDTA, a metal chelator, inhibits it. When trace levels of transition metals are present, low concentrations of ascorbic acid can elevate ceroid formation. This pro- and antioxidant characteristic of ascorbic acid was confirmed by monitoring the generation of oxidants by various concentrations of ascorbic acid, assessed by benzoic acid hydroxylation or the fragmentation of BSA. We discuss these observations in the context of an apparent increase in ascorbic acid oxidation and elevated severity of atherosclerosis in diabetes mellitus.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cells, Cultured; Ceroid; Cholesterol Esters; Copper; Diabetes Complications; Diabetes Mellitus; Edetic Acid; Humans; Macrophages; Male; Mice; Mice, Inbred BALB C; Oxidation-Reduction; Serum Albumin, Bovine

The aim of this study was to investigate the relationship between dietary ascorbic acid intake and serum lipid concentration in the aged. The amount of dairy food intake for three consecutive days were measured and the serum levels of total-cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDLC) were determined 279 subjects (135 males and 135 females), 65 years and over living in one community. The LDL-cholesterol (LDLC) was calculated by (TC-HDLC)-TG x 0.2. Dietary ascorbic acid intake showed no significantly difference between males and females, but had a significantly positive correlation with HDLC, the intake of carbohydrates and protein and total fat. However it had a significantly negative correlation with LDLC and LDLC/HDLC. Multiple regression analysis showed that dietary ascorbic acid intake had a statistically significant relationship with HDLC, LDLC and LDLC/HDLC. Since HDLC, which is known to be an anti-atherogenic, was related to increase in the dietary ascorbic acid intake, and LDLC, which is known to be an atherogenic, was related to its decrease, it was suggested that dietary ascorbic acid intake might have an important effect on the genesis and prevention of atherogenic diseases.

Topics: Aged; Aged, 80 and over; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, HDL; Diet; Female; Humans; Male; Nutrition Assessment; Triglycerides

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Humans; Lipid Peroxidation; Lipoproteins, LDL; Rats; Vitamin E; Vitamin E Deficiency

The biochemical mechanisms by which hypertension accelerates atherosclerosis and increases the risk of aortic aneurysm rupture are poorly understood. This study evaluates the effects of hypertension on aortic trace element concentrations and antioxidant status in tissue removed from 26 normotensive (NT) and 20 hypertensive (HT) patients. Twenty-seven of 46 patients (59%) had aneurysmal (AA), and 19 of 46 (41%) had occlusive disease (OD). Aortic iron concentrations were markedly higher in both OD and AA tissue compared with controls. A similar trend was observed with copper concentrations, with the highest elevations observed in HT AA tissues. No significant differences were observed in zinc concentrations, except that HT AA aorta had significantly lower zinc levels than either OD or control tissue. Aortic ascorbic acid concentrations in diseased aorta were lower than those of controls, but independent of blood pressure. Copper-zinc-superoxide dismutase activity was similarly reduced, with the lowest activity observed in diseased aorta from HT patients. Only HT AA aorta had significantly higher manganese-superoxide dismutase activity than controls. The aortas of patients with AA had significantly lower amounts of elastin and greater elastase activity than either controls or those with OD. However, the differences were independent of blood pressure. Hypertensive patients with OD and AA had 31% more and 27% less aortic collagen, respectively, than their NT counterparts (P less than 0.05). These data suggest that the reduction in aortic collagen and elastin in HT patients with AA compared with their NT counterparts may explain the larger size of aneurysms and predispose to their eventual rupture. Furthermore, the diminished antioxidant status associated with HT predisposes to lipid peroxidation, which contributes to the acceleration of these processes. Our studies were conducted in patients with established aortic aneurysmal and occlusive disease. Whether these observations are pertinent to the pathogenesis of AA and OD remains unclear and merits further study.

Topics: Antioxidants; Aorta; Aortic Aneurysm; Arteriosclerosis; Ascorbic Acid; Blood Pressure; Collagen; Copper; Elastin; Humans; Hypertension; Iron; Lipid Peroxidation; Male; Superoxide Dismutase; Trace Elements; Zinc

Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.

Topics: Anticoagulants; Arteriosclerosis; Ascorbic Acid; Cells, Cultured; Dextran Sulfate; Dose-Response Relationship, Drug; Endothelium, Vascular; Factor VII; Factor X; Humans; In Vitro Techniques; Lipoproteins, LDL; Oxidation-Reduction; Polysaccharides; Probucol; Protein C; Thromboplastin

The concept that lipoprotein(a) [Lp(a)] is a surrogate for ascorbate is suggested by the fact that this lipoprotein is found generally in the blood of primates and the guinea pig, which have lost the ability to synthesize ascorbate, but only rarely in the blood of other animals. Properties of Lp(a) that are shared with ascorbate, in accordance with this hypothesis, are the acceleration of wound healing and other cell-repair mechanisms, the strengthening of the extracellular matrix (e.g., in blood vessels), and the prevention of lipid peroxidation. High plasma Lp(a) is associated with coronary heart disease and other forms of atherosclerosis in humans, and the incidence of cardiovascular disease is decreased by elevated ascorbate. Similar observations have been made in cancer and diabetes. We have formulated the hypothesis that Lp(a) is a surrogate for ascorbate in humans and other species and have marshaled the evidence bearing on this hypothesis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Biological Evolution; Cardiovascular Diseases; Diabetes Mellitus; Disease Models, Animal; Humans; Lipoprotein(a); Lipoproteins; Neoplasms; Wound Healing

Topics: Adult; Aged; alpha-Tocopherol; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cytochrome c Group; Drug Therapy, Combination; Female; Humans; Leg; Lipid Peroxidation; Male; Middle Aged; Tocopherols; Vitamin E

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Cholesterol, Dietary; Guinea Pigs; Lipids; Male

Topics: Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cardiovascular Diseases; Chronic Disease; Czechoslovakia; Diet; Humans

Feeding a cholesterol-rich diet (0.3%) to rabbits resulted in an intimal thickening and lipid infiltration of the aorta. The prostacyclin production by the vascular endothelium was significantly decreased, after a transient increase after 2 weeks of diet. The arachidonic acid metabolism in platelets was hardly changed. Addition of a low dose vitamin C (150 mg/day) to the cholesterol rich diet resulted in decreased lipid infiltration and intimal thickening and the transient increase of the prostacyclin production was postponed to the 4th week. Although this dose of vitamin C could not restore the decreased prostacyclin production observed after 6 weeks diet, a higher dose of vitamin C (600 mg/day), besides its beneficial effect on the lipid infiltration and the intimal thickening in the thoracic aorta, kept the intimal prostacyclin production at normal levels for at least 8 weeks.

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Endothelium; Epoprostenol; Liver; Male; Rabbits; Vitamin E

This article suggests that atherosclerosis is a plurideficiency disease. Increasing only linoleic acid intake in daily nutrition to counteract atherosclerosis has failed to give satisfactory results. The use of lecithin affects the metabolism and transportation of cholesterol in the blood more efficiently than do the polyunsaturated fats. Furthermore, insufficient quantities of vitamins B6 and C in the blood contribute to lesions of the arterial endothelium, which are indistinguishable from the first stages of atherosclerosis. It is recommended, therefore, that these factors should be combined, and that, together with a sufficient quantity of polyunsaturated fatty acids, the daily diet be supplemented with adequate doses of lecithin, vitamin B6 (in B complex), and vitamin C.

Topics: Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Humans; Nutritional Physiological Phenomena; Phosphatidylcholines; Pyridoxine; Risk; Vitamin B 6 Deficiency

Feeding rabbits a cholesterol-rich diet (0.3%) resulted in morphological changes and a decrease in the prostacyclin production by the aortic endothelium. Addition of vitamin C (0.1%) to the cholesterol-rich diet resulted in a decreased lipid infiltration and intimal thickening. Although there was a tendency to restore the prostacyclin output, vitamin C, in the amount administered, was unable to completely normalise the endothelial PGI2 production.

Topics: Animals; Aorta; Aorta, Thoracic; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Ascorbic Acid; Cholesterol, Dietary; Endothelium; Rabbits

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Female; Hypercholesterolemia; Male; Plants, Medicinal; Rabbits

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Clofibrate; Diet; Drug Interactions; Humans; Hypercholesterolemia; Lipid Metabolism; Nicotinic Acids; Phospholipids

Topics: Adolescent; Adult; Aged; Amniocentesis; Amniotic Fluid; Arteriosclerosis; Ascorbic Acid; Child; Child, Preschool; Chromosome Aberrations; Dementia; Female; Folic Acid; Glutathione; Humans; Infant; Middle Aged; Mutagens; Neoplasms; Pregnancy; Tretinoin

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cattle; Endothelium; Female; Glycosaminoglycans; Insulin; Myocardium; Pregnancy; Retinal Diseases

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cholesterol; Guinea Pigs; Humans; Hypolipidemic Agents; Mice

The favourable action of phospholipids and of Vitamin C in reverting the process of atherogenesis, already repeatedly described in the literature, was explored by the authors in applying an association of these two substances in experimental atherosclerosis. The obtained results not only confirm, once again, the prophylactic and therapeutic activity of phospholipids and vitamin C, but also demonstrate that these components, when associated, lead to much better results in the prevention and resolution of atheromatous plaques provoked in rabbits by cholesterol-feeding.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Diet, Atherogenic; Drug Therapy, Combination; Phospholipids; Rabbits

The ascorbic acid level of the leukocytes in patients with coronary artery disease was compared to the ascorbic acid level of the leukocytes in patients without coronary artery disease as demonstrated by coronary arteriography. The leukocyte ascorbic acid level was found significantly lower in patients with coronary arteriography. The leukocyte ascorbic acid level was found significantly lower in patients with coronary atherosclerosis (P < 0.001). There was also significant difference in the leukocyte ascorbic acid levels among patients with abnormal coronary arteriograms who smoked compared to those who did not. The anatomical changes secondary to atherosclerotic disease, and mainly those changes related to the ground substance, have been shown to be the changes that have been observed in patients with ascorbic acid deficiency. From the present study, with its limitations, it is suggested that ascorbic acid may play a role in the pathogenesis of atherosclerosis, and although not implicated as an etiological factor in coronary artery disease, it suggests that a closer look at its possible role in the pathogenesis and progression of coronary artery disease is warranted.

Topics: Adult; Aged; Aging; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cardiac Catheterization; Coronary Disease; Female; Humans; Leukocytes; Male; Middle Aged; Sex Factors; Smoking

The effects of L-ascorbic acid on 35S-incorporation into thoracic aorta glycosaminoglycans and upon aorta cholesterol levels were determined in hypercholesterolemic rabbits. No significant difference was observed in serum free or esterified cholesterol levels between animals receiving L-ascorbic acid supplementation or saline while maintained on a cholesterol diet (0.5%). A 15-fold higher serum cholesterol was observed in animals on the cholesterol diet to those animals which received a normal rabbit (Purina) diet. L-Ascorbic acid increased sulfated glycosaminoglycans concentrations in hypercholesterolemic rabbits which paralleled lower tissue free and esterified cholesterol levels. The 35S-specific activity of glycosaminoglycans in hypercholesterolemic animals receiving saline was much greater than in those animals receiving L-ascorbic acid. This suggests that L-ascorbic acid plays a role in the maintenance of adequate levels of aortic sulfated glycosaminoglycans. This then is a suggested biochemical mechanism of L-ascorbic acids interaction in the atherogenic process.

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Cholesterol; Glycosaminoglycans; Hypercholesterolemia; Male; Rabbits; Sulfur Radioisotopes

Five-week old, male, Japanese quail (Coturnix coturnix japonica) were given ad libitum access to glucose- soybean meal-10% fat diets containing 0, 0.25, 0.5, or 1% cholesterol, with or without the addition of a vitamin supplement (vitamin C--1 g/kg of diet, vitamin E--30 I.U./kg of diet and choline chloride--5.5 g/kg of diet). After 12 weeks, 9 quail from the 24 quail fed each diet were killed and the total cholesterol concentration of serum, liver, kidney, and aorta was determined. Cholesterol concentrations of these organs increased with increasing levels of dietary cholesterol. The vitamin supplementation enhanced the increase in the cholesterol concentration of serum and kidney, lessened the elevation of the liver cholesterol concentration and had no effect on the aorta cholesterol concentration. The remaining quail were fed the same diets, for a subsequent 12 week period, except that cholesterol was deleted. At the termination of the experiment, the total cholesterol concentration of serum, liver, and kidney returned to control level for all treatments in which organ cholesterol concentrations had been increased previously. Aortic cholesterol concentration decreased during the second 12 week period (0.5 and 1% cholesterol diets fed for the first 12 weeks), however, the aortic cholesterol concentration remained higher than those of the control at 24 weeks. No significant effect of vitamin supplementation on organ cholesterol concentration was noted at 24 weeks although serum cholesterol concentration was significantly lower for the vitamin- fed groups at all levels of dietary cholesterol. Aortic ahteromata were observed at both 12 and 24 weeks in all groups fed 0.5 and 1% cholesterol.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Choline; Coturnix; Disease Models, Animal; Kidney; Liver; Male; Vitamin E

Topics: Arteriosclerosis; Ascorbic Acid; History, 18th Century; History, 20th Century; Humans; Motor Activity

Effects of L-ascorbate 2-sulfate (AAS) on lipid metabolism and on pathological changes of aorta and visceral organs were investigated in cholesterol fed rabbits, with ascorbic acid (AA) and clofibrate (CPIB) as reference compounds. Administration of AAS (300 and 150 mg/kg) inhibited an increase in the levels of serum total cholesterol, free cholesterol, triglycerides and phospholipids caused by cholesterol feeding. A high dose of AAS prevented an increase of liver weight. An increase in the level of liver cholesterol was inhibited by a high dose of AAS. Both doses of AAS effectively prevented an accumulation of cholesterol in the aorta. The area rate of atheromatous plaque in aorta was less in specimens from both groups of AAS than in those from control I. Pathological changes in intima and media of aorta were milder in specimens from both groups of AAS. Developed of patholoigcal changes in arteries of various organs were prevented with both doses of AAS.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Body Weight; Cholesterol; Clofibrate; Hypolipidemic Agents; Liver; Male; Phospholipids; Rabbits; Triglycerides

Topics: Adolescent; Adult; Aged; Arteriosclerosis; Ascorbic Acid; Cholesterol; Humans; Hypercholesterolemia; Lipids; Middle Aged; Nutritional Physiological Phenomena; Poland

Topics: Adolescent; Adult; Arteriosclerosis; Ascorbic Acid; Cholesterol; Common Cold; Double-Blind Method; Humans; Middle Aged; Neoplasms; Placebos

Rabbits were randomly assigned to two groups. Age and body weight distribution were equal in both groups. All animals were placed on a high cholesterol diet for 9 wk, then returned to a normal diet for 1 wk. At the end of this dietary regimen, one group of animals received subcutaneous injections of psysiological saline 3 times/day, 5 days/wk for 10 wk, and the other group recieved L-ascorbate 2-sulfate (0.37 mmole) according to the same timetable. On alternate weeks, the serum levels of total and free cholesterol were determined. After 10 wk of treatment the animals were killed; the plaques were excised from the aortas and examined for total mass and cholesterol content. We observed that, under these dietary conditions, L-ascorbate 2-sulfate does not mobilize cholesterol or its esters from preformed aortic plaque. However, we did observe that animals showing high cholesterol levels in their sera died prematurely when injected with L-ascorbate 2-sulfate. Gross and histopathological investigations of organs and tissues did not reveal any significant differences among the animals that died prematurely and those that survived to the termination of the experiment.

Topics: Animals; Aortic Diseases; Arteriosclerosis; Ascorbic Acid; Cholesterol; Diet, Atherogenic; Drug Evaluation, Preclinical; Injections, Subcutaneous; Male; Rabbits; Saline Solution, Hypertonic

Effects of intravenously injected L-ascorbic acid or L=ascorbic acid 2-sulfate on aortic intimal thickening were examined histologically, qualitatively, and quantitatively in the upper, middle and lower thoracic aortic positions of cholesterol-induced atherosclerotic rabbits. A means of evaluating the degree of pathology of the aortic positions was developed employing five descriptive statistics of intimal thickening. Both L-ascorbic acid and L-ascorbic acid 2-sulfate inhibited intimal thickening. The most significant reductions were observed in the upper thoracic aorta.

Topics: Adrenal Glands; Animals; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Ascorbic Acid; Cholesterol; Injections, Intravenous; Liver; Male; Rabbits; Spleen; Sulfates

Rabbits on a high cholesterol diet were divided into three groups: one group received subcutaneous injections of physiological saline 3 times/day, 5 days/wk for 10 wk; another group received subcutaneous injections of L-ascorbic acid (0.37 mmole) according to the same timetable; and the third group was administered an equivalent amount of L-ascorbate 2-sulfate as outlined above. Each week the serum levels of total and free cholesterol and triglycerides were measured. At the end of 10 wk the animals were killed and the cholesterol content of the livers, spleens, and adrenal glands was measured. The aortas were examined for plaque deposition; the deposits were excised and pooled according to groups; and the total mass and cholesterol contents of the pooled plaques were determined. Administration of ascorbic acid or ascorbate 2-sulfate did not prevent hypercholesterolemia or elevated levels of serum triglycerides. No significant differences among the groups were found either in tissue cholesterol levels or in the extent or type of lesions found. Although plaque deposition appeared to be similar in the aortas of these animals, a marked difference was found in total mass and cholesterol content of the plaques: The plaques of the saline-treated group had a total mass and cholesterol content approximately 2.5 times that found in the group injected with ascorbic acid and about 1.5 times that found in the animals treated with ascorbate 2-sulfate. These results indicate that ascorbic acid, in particular, minimizes the total quantity of plaque deposition even though it is ineffective in preventing hypercholesterolemia, elevated serum triglycerides, and accumulation of cholesterol by several tissues.

Topics: Adrenal Glands; Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Hypercholesterolemia; Hyperlipidemias; Liver; Male; Rabbits; Spleen; Sulfates; Triglycerides

Topics: Arteriosclerosis; Ascorbic Acid

Topics: Age Factors; Anemia, Hypochromic; Animals; Arteriosclerosis; Ascorbic Acid; Attitude to Health; Australia; Breast Feeding; Child; Food Additives; Humans; Infant; Infant Food; Infant Nutritional Physiological Phenomena; Infant, Newborn; Iron; Metric System; Milk; Obesity; Vitamin D; Weaning

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Disease Models, Animal; Guinea Pigs; Humans; Lipid Metabolism; Scurvy; Time Factors

Topics: Adult; Agriculture; Arteriosclerosis; Ascorbic Acid; Child; Cholesterol, Dietary; Coffee; Coronary Disease; Diet; Diet Therapy; Dietary Fats; Fats, Unsaturated; Humans; Lipid Metabolism; Lipoproteins; Male; Vitamin E; Water

Topics: Arteriosclerosis; Ascorbic Acid; Cholesterol, Dietary; Chromium; Coronary Disease; Diet, Atherogenic; Dietary Carbohydrates; Humans; Water Supply

Topics: Arteriosclerosis; Ascorbic Acid; Blood Vessels; Cholesterol; Female; Humans; Male; Thrombophlebitis

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholesterol; Coronary Disease; Humans

Topics: Aged; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholesterol; Coronary Disease; Female; Humans; Male; Middle Aged; Thrombosis

Topics: Adult; Aged; Arteriosclerosis; Ascorbic Acid; Cadmium; Cholesterol; Deficiency Diseases; Female; Humans; Hypertension; Male; Middle Aged; Smoking

Topics: Aminobenzoates; Animals; Arteries; Arteriosclerosis; Ascorbic Acid; Biotin; Carotenoids; Chickens; Choline; Dogs; Folic Acid; Humans; Inositol; Nicotinic Acids; Pyridoxine; Rabbits; Riboflavin; Thiamine; Vitamin A; Vitamin B 12; Vitamin E; Vitamins

Topics: Adult; Animals; Arteriosclerosis; Ascorbic Acid; Cholesterol; Diet, Atherogenic; Female; Guinea Pigs; Humans; Hypercholesterolemia; Male; Middle Aged; Rabbits; Time Factors

Topics: Arteriosclerosis; Ascorbic Acid; Cholesterol; Hypercholesterolemia; Time Factors

Topics: Arteriosclerosis; Ascorbic Acid; Cholesterol; Humans; Male; Middle Aged

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Carbon Isotopes; Cholesterol; Guinea Pigs; Oxidation-Reduction

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cholesterol; Humans; Liver; Male; Middle Aged

Topics: Aged; Aging; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Back Pain; Common Cold; Humans; Mental Disorders; Nutritional Requirements; Pituitary-Adrenal System; Renal Dialysis; Shock, Traumatic; Stress, Physiological; Structure-Activity Relationship; Surgical Procedures, Operative

Topics: Arteriosclerosis; Ascorbic Acid; Common Cold; Humans; Methemoglobinemia

Following the chance observation that the author's serum-cholesterol could be varied between 140 and 230 mg. per 100 ml. by increasing the vitamin-C intake or by lowering it, a study was undertaken in healthy individuals and in patients with atherosclerosis. In healthy people under the age of 25, cholesterol levels tended to fall when 1 g. of vitamin C per day was added to an otherwise normal diet. In older people, no consistent pattern of serum-cholesterol change was seen, but in patients with a history of atherosclerosis, most of whom were on clofibrate and/or anticoagulants, the serum-cholesterol increased in the weeks when vitamin-C supplements increased in the weeks when vitamin-C supplements were given. It is suggested that this rise in serum-cholesterol is caused by mobilisation of the arterial cholesterol.

Topics: Adult; Age Factors; Anticoagulants; Arteriosclerosis; Ascorbic Acid; Cholesterol; Clofibrate; Female; Humans; Male; Middle Aged

Topics: Adenosine Triphosphate; Aminobutyrates; Animals; Arteriosclerosis; Ascorbic Acid; Carbon Isotopes; Glycoproteins; Growth; Guinea Pigs; Homocysteine; In Vitro Techniques; Lactones; Microsomes, Liver; Phosphorus Isotopes; Scurvy; Skin; Sulfates; Sulfonic Acids; Sulfur Isotopes; Thiophenes

Topics: Adrenal Glands; Animals; Arteriosclerosis; Ascorbic Acid; Carbon Dioxide; Carbon Isotopes; Cholesterol; Guinea Pigs; Injections, Intraperitoneal; Liver; Time Factors

Topics: Age Factors; Animals; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholesterol; Coronary Disease; Diet, Atherogenic; Electrocardiography; Fibroblasts; Guinea Pigs; Humans; Intracranial Arteriosclerosis; Time Factors

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Cholesterol; Humans; Lipid Metabolism; Male; Peroxides; Rabbits; Rats; Sulfhydryl Compounds

Topics: Animals; Antioxidants; Aorta; Arteriosclerosis; Ascorbic Acid; Cholesterol; Humans; Liver; Polarography; Rabbits; Sulfhydryl Compounds

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Hydrogen; Male; Oxidation-Reduction; Rabbits; Sulfides

Topics: Arteriosclerosis; Ascorbic Acid; Cholesterol; Humans; Oxygen Consumption; Smoking

Topics: Acetates; Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Carbon Isotopes; Cholesterol; Intestine, Small; Male; Myocardium; Rabbits

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Lipid Metabolism; Male; Rats

Topics: Adrenal Glands; Animals; Arteriosclerosis; Ascorbic Acid; Carbon Isotopes; Cholesterol; Kidney; Male; Pancreas; Rabbits

Topics: Adult; Aged; Arteriosclerosis; Ascorbic Acid; Cholinesterases; Female; Humans; Male; Middle Aged

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Bile; Cholesterol; Liver; Male; Rabbits

Topics: Adrenal Glands; Animals; Arteriosclerosis; Ascorbic Acid; Body Weight; Cholesterol; Disease Models, Animal; Histocytochemistry; Hypercholesterolemia; Lipids; Male; Methods; Organ Size; Rabbits; Time Factors

Topics: Acute Disease; Adrenal Glands; Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Brain Chemistry; Cholesterol; Diet, Atherogenic; Fatty Acids; Guinea Pigs; Intestine, Small; Liver; Male; Models, Biological; Phospholipids; Scurvy

Topics: Animals; Aorta; Aortic Diseases; Arteriosclerosis; Ascorbic Acid; Collagen; Epinephrine; Hydroxyproline; Iron; Ketoglutaric Acids; Kinetics; Liver; Male; Mixed Function Oxygenases; Organ Specificity; Proline; Rabbits; Rats; Species Specificity; Stimulation, Chemical; Thyroxine; Tritium; Water

Topics: Adult; Aged; Arteriosclerosis; Ascorbic Acid; Calcium; Cholesterol; Coronary Disease; Electrocardiography; Female; Gluconates; Humans; Hypothyroidism; Male; Middle Aged; Niacinamide; Pantothenic Acid; Riboflavin; Thiamine; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroxine; Vitamin B 12

Topics: Adrenal Glands; Animals; Arteriosclerosis; Ascorbic Acid; Body Weight; Cholesterol; Cold Temperature; Diet, Atherogenic; Environmental Exposure; Hypercholesterolemia; Lipid Metabolism; Liver; Male; Organ Size; Rabbits

Topics: Arteriosclerosis; Ascorbic Acid; Cholesterol; Humans; Lipoprotein Lipase; Tongue; Triglycerides

Topics: Animals; Anticholesteremic Agents; Arteriosclerosis; Ascorbic Acid; Cholesterol; Diet, Atherogenic; Lipids; Rabbits

Topics: Adrenal Glands; Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Bile; Carbon Isotopes; Erythrocytes; Hypercholesterolemia; Intestine, Small; Kidney; Liver; Lung; Male; Methods; Myocardium; Pancreas; Rabbits; Spleen; Testis

Topics: Animals; Arteriosclerosis; Ascorbic Acid

Topics: Adolescent; Adult; Aged; Animals; Arteriosclerosis; Ascorbic Acid; Cholesterol; Female; Glycerides; Humans; Lipid Metabolism; Lipoprotein Lipase; Male; Middle Aged; Rabbits; Rats; Serotonin; Triglycerides

Topics: Adenosine Triphosphate; Aged; Arteriosclerosis; Ascorbic Acid; Drug Synergism; Fibrinolytic Agents; Heparin; Humans; Lipotropic Agents; Nicotinic Acids; Regional Blood Flow

Topics: Aged; Angiomatosis; Arteriosclerosis; Ascorbic Acid; Glomerulonephritis; Humans; Hypertension; Keratosis; Male; Nails; Pressure; Purpura

Topics: Adenosine Triphosphate; Arteriosclerosis; Ascorbic Acid; Blood Coagulation Disorders; Fibrinolytic Agents; Heparin; Humans; Inositol; Nicotinic Acids; Thrombosis

Topics: Adrenal Glands; Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Carbon Isotopes; Cholesterol; Hypercholesterolemia; Intestine, Small; Kidney; Lipoproteins; Liver; Lung; Male; Methods; Models, Biological; Myocardium; Pancreas; Rabbits; Spleen; Testis

Topics: Anticholesteremic Agents; Arteriosclerosis; Ascorbic Acid; Cholesterol; Drug Synergism; Heparin; Humans; Inositol; Lipoproteins; Middle Aged; Nicotinic Acids; Vitamin B Complex

Topics: Adult; Aged; Aging; Animals; Arteriosclerosis; Ascorbic Acid; Blood Pressure Determination; Cholesterol; Glycerides; Humans; Lipoprotein Lipase; Middle Aged; Rabbits; Rats; Serotonin; Triglycerides

Topics: Aged; Arteriosclerosis; Ascorbic Acid; beta-Lipotropin; Fibrinolytic Agents; Heparin; Humans; Middle Aged; Nicotinic Acids; Pituitary Hormones, Anterior; Thromboembolism

Topics: Aged; Arteriosclerosis; Ascorbic Acid; Extremities; Folic Acid; Humans; Middle Aged; Vitamin B Complex

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Flavonoids; In Vitro Techniques; Male; Poultry

Topics: Arteriosclerosis; Ascorbic Acid; Cholesterol; Coronary Vessels; Humans; Hypercholesterolemia; Hypertension; Hypertension, Renal; Kidney; Vitamins

Topics: Animals; Aorta; Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Blood Proteins; Cholesterol; Chromium Isotopes; Dietary Fats; Hypercholesterolemia; Lipid Metabolism; Liver; Rabbits; Research

Topics: Anemia; Arteriosclerosis; Ascorbic Acid; Humans; Intracranial Arteriosclerosis; Liver Diseases; Mental Disorders; Pyridoxine; Vitamins

Topics: Aging; Aortic Diseases; Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Calcium; Hexosamines; Histocytochemistry; Hydroxyproline; Lipidoses; Lipids; Pathology; Research

Topics: Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Atherosclerosis; Biomedical Research; Drug Therapy; Humans; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Calcium; Calcium, Dietary; Drug Therapy; Folic Acid; Geriatrics; Humans; Iron; Magnesium; Myocardial Infarction; Preventive Medicine; Procaine; Vitamin B Complex

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Cholesterol; Gastric Mucins; Humans; Lipids; Niacinamide; Pyridoxine; Vitamin A; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Cholesterol; Humans

Topics: Arteriosclerosis; Ascorbic Acid; Blood Chemical Analysis; Cardiovascular Diseases; Coronary Disease; Geriatrics; Heart Failure; Humans; Hypertension

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Humans; Methionine; Phenobarbital; Pyridoxine

Topics: Arteriosclerosis; Ascorbic Acid; Cerebrovascular Disorders; Drug Combinations; Folic Acid; Minerals; Procaine; Vitamin B Complex; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Basal Metabolism; Corrinoids; Hematinics; Humans; Vitamin B 12; Vitamin B Complex; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Calcium; Cholesterol; Humans; Hypercholesterolemia; Vitamins

Topics: Aorta; Arteriosclerosis; Ascorbic Acid

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Essential Hypertension; Humans; Hypertension; Lipids

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Humans; Iodides; Iodine; Thyroid Gland; Viscera; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Coronary Disease; Coronary Vessels; Diuretics; Humans; Vitamins

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Chickens; Meat; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Drug-Related Side Effects and Adverse Reactions; Vitamins

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Cholestanes; Cholesterol; Cortisone; Heart Diseases; Rats; Sclerosis; Vitamin D; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Choline; Fibrinogen; Humans; Iodine; Prothrombin; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Iodine

Topics: Acid-Base Equilibrium; Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Cholesterol; Humans; Hypertension; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Humans; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Cholesterol; Humans; Vitamin B 12; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Humans; Prothrombin; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Biomedical Research; Humans; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Tunica Intima

Topics: Arteriosclerosis; Ascorbic Acid; Humans; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Inositol; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Humans; Vitamin A; Vitamins

Topics: Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Blood; Cholesterol; Humans; Hypertension; Vitamins