linoleic-acid and Arteriosclerosis

Essential fatty acids (EFAs)--linoleic acid (LA) and alpha-linolenic acid (ALA) are critical for human survival. EFAs are readily available in the diet. But, to derive their full benefit, EFAs need to be metabolized to their respective long-chain metabolites. EFAs not only form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), but also give rise to lipoxins (LXs), resolvins, isoprostanes, and hydroxy- and hydroperoxyeicosatetraenoates. Certain PGs, TXs, and LTs have pro-inflammatory actions whereas LXs and resolvins are anti-inflammatory in nature. Furthermore, EFAs and their long-chain metabolites modulate the activities of angiotensin converting and HMG-CoA reductase enzymes, enhance acetylcholine levels in the brain, increase the synthesis of endothelial nitric oxide, augment diuresis, and enhance insulin action. Thus, EFAs and their metabolites may function as endogenous ACE and HMG-CoA reductase inhibitors, nitric oxide enhancers, beta-blockers, diuretics, anti-hypertensive, and anti-atherosclerotic molecules. In addition, EFAs and their long-chain metabolites react with nitric oxide (NO) to yield respective nitroalkene derivatives that exert cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors (PPARs). Thus, EFAs and their derivatives have varied biological actions that may have relevance to their involvement in several physiological and pathological processes.

Topics: alpha-Linolenic Acid; Arteriosclerosis; Fatty Acids, Essential; Humans; Inflammation; Linoleic Acid; Metabolic Syndrome

Type 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently, data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism. These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the pathogenesis of diabetic vascular disease. Evidence suggests that inflammatory responses in the vasculature can be elicited by small oxidized lipids that are components of oxidized low-density lipoprotein or products of the lipoxygenase and cyclooxygenase pathways of arachidonic and linoleic acid metabolism. This review evaluates these inflammatory and proatherogenic pathways in the pathogenesis of diabetic vascular disease.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Chemotaxis; Coronary Restenosis; Cyclooxygenase 2; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Gene Expression Regulation; Humans; Hydroxyeicosatetraenoic Acids; Inflammation Mediators; Insulin Resistance; Linoleic Acid; Lipoxygenase; Membrane Proteins; Mice; Models, Biological; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Signal Transduction

Conjugated Linoleic Acids (CLA) are of great interest for analysts since techniques have been developed to determine the dietary occurrence of CLA with a good accuracy. CLA is found in animal products from ruminant sources as the result of biohydrogenation of polyunsaturated fatty acids in the rumen and as the consequence of the delta-9 desaturation of vaccenic acid in animal tissues. CLA can also be obtained in the laboratory by isomerisation of linoleic acid or by total chemical synthesis. While the "natural" isomer is rumenic acid (9c,11t-18:2), synthetic mixtures contain mainly two isomers: the 9c,11t- and the 10t,12c-18:2. Although CLA have been shown to be metabolized into desaturated and chain elongated products, it remains unclear whether these so-formed conjugated metabolites may be involved in the effects of CLA on fatty acid metabolism. Experiments carried out on animal models with CLA have shown different health benefits: anticarcinogenic, antiatherosclerotic effects, modulation of body composition , the "natural" CLA (9c,11t-18:2) being closely related to the protection against cancer and the 10t,12c-18:2 to the reduction of the fat mass. Nevertheless, recent findings have suggested adverse effects in mice. Most of the studies carried out on humans concern the influence of CLA on body composition and its possible inverse association with cancer. Since the results are still controversial and since very few data dealing with the safety of using CLA in long term feeding studies have so far been published, further works are warranted to consider the benefits of CLA for humans.

Topics: Animals; Arteriosclerosis; Body Composition; Disease Models, Animal; Humans; Linoleic Acid; Linoleic Acids, Conjugated; Neoplasms; Oleic Acids; Trans Fatty Acids

Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of linoleic acid that has been shown to suppress the development of atherosclerosis in a rabbit model. We investigated whether CLA acts as a cyclo-oxygenase (COX) inhibitor or as an agonist of the peroxisome-proliferator-activator receptor (PPAR) gamma in the ApoE(-/-) mouse model. In vitro, a 9-cis, 11-trans isomer of CLA inhibited prostaglandin formation and oxygen consumption by both isoforms of COX, with no evidence by MS of alternative products being generated. In vivo, supplementation with CLA was found to induce resolution of atherosclerosis. The effect of CLA in vivo could not be explained by COX inhibition alone, as urinary prostaglandin levels were unchanged in animals receiving CLA supplementation, and administration of selective COX inhibitors did not induce lesion regression. There was however induction of PPAR gamma, a known response to agonists of this nuclear orphan receptor.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Cell Nucleus; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Eicosanoids; Enzyme Inhibitors; Humans; Isoenzymes; Linoleic Acid; Membrane Proteins; Mice; Models, Biological; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Protein Isoforms; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids found in beef, lamb, and dairy products that exist as positional and stereo-isomers of octadecadienoate (18:2). Over the past two decades numerous health benefits have been attributed to CLA in experimental animal models including actions to reduce carcinogenesis, atherosclerosis, onset of diabetes, and body fat mass. The accumulation of CLA isomers and several elongated/desaturated and beta-oxidation metabolites have been found in tissues of animals fed diets with CLA. Molecular mechanisms of action appear to include modulation of eicosanoid formation as well as regulation of the expression of genes coding for enzymes known to modulate macronutrient metabolism. This review focuses on health benefits, metabolism, and potential mechanisms of action of CLA and postulates the implications regarding dietary CLA for human health.

Topics: Adipose Tissue; Animals; Arteriosclerosis; Dairy Products; Diabetes Mellitus; Diet; Dietary Fats, Unsaturated; Disease Models, Animal; Humans; Linoleic Acid; Meat; Mice; Neoplasms; Rats; Stereoisomerism

Conjugated linoleic acid is a collective name for mixtures of several positional and geometric conjugated dienoic isomers of linoleic acid, which have been shown to impact favorably on several biological processes, particularly carcinogenesis. Recent studies have clearly established that the c9, t11 and t10, c12 isomers have distinct biological effects. The latter may be of particular importance in affecting blood lipids. Because conjugated linoleic acid has been suggested to be anti-atherogenic, this review is focused on its effects on cardiovascular function. Careful scrutiny of the literature suggests that at present it is premature to assign any beneficial role to conjugated linoleic acid in terms of its ability to impact either blood lipids or atherogenesis.

Topics: Animals; Arteriosclerosis; Cardiovascular Physiological Phenomena; Humans; Linoleic Acid; Lipids

N-6 fatty acids are essential for normal growth, development and health, and so extreme care is necessary before deciding that they are harmful. Theoretical and epidemiological evidence suggests the involvement of n-6 polyunsaturated fatty acids (PUFAs) in disease progression or prevention; however, n-6 function cannot be considered in isolation but needs to be seen as part of the complex of nutrient interactions with n-3 fatty acids (which compete for the same enzymatic pathways) and antioxidants. Insulin sensitivity might be the common factor relating disease to fatty acid metabolism both within and between the fatty acid pathways. High linoleate to arachidonate concentrations have been observed in insulin resistance, diabetic complications and some tumours, but these are multifactorial processes that include many lifestyle determinants and it is therefore wrong to condemn only n-6 fatty acids in their etiology. The results based on the criteria for assessing diet and disease are still insufficient to declare n-6 fatty acids a serious health risk; at most, the verdict should be "not proven". The question may never be conclusively answered not only because prospective dietary intervention trials (unlike those with n-3 fish oil capsules) are fraught with dosage and compliance problems, but also because of high background linoleate consumption. Tissue fatty acid composition may be a suitable biomarker for PUFA intake but there are many theoretical and methodological problems concerning other suitable markers because of the multiplicity of their biological effects. Before making evidence-based dietary recommendations, future research should consider: 1) how n-3 and n-6 dietary PUFAs affect the physiological balance (dose-response) of their derivatives such as eicosanoids and the newly-discovered fatty acid amides; 2) the metabolic interactions between n-6 and n-3 fatty acid pathways (including gene-nutrient effects); 3) the need for antioxidant cover (quantity and quality); 4) prospective intervention trials.

Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Humans; Insulin Resistance; Linoleic Acid; Neoplasms

Conjugated linoleic acid (CLA), a derivative of a fatty acid linoleic acid (LA), has been reported to decrease tumorigenesis in animals. CLA is unique because unlike most antioxidants which are components of plant products, it is present in food from animal sources such as dairy foods and meats. CLA concentrations in dairy products typically range from 2.9 to 8.92 mg/g fat of which the 9-cis, 11-trans isomer makes up to 73% to 93% of the total CLA. Low concentrations of CLA are found in human blood and tissues. In vitro results suggest that CLA is cytotoxic to MCF-7 cells and it inhibits the proliferation of human malignant melanoma and colorectal cancer cells. In animal studies, CLA has inhibited the development of mouse epidermal tumors, mouse forestomach cancer and rat mammary cancer. Hamsters fed CLA collectively had significantly reduced levels of plasma total cholesterol, non-high-density lipoprotein cholesterol, (combined very-low and low-density lipoprotein) and triglycerides with no effect on high-density lipoprotein cholesterol, as compared to controls. Dietary CLA modulated certain aspects of the immune defense but had no obvious effect on the growth of an established, aggressive mammary tumor in mice. It is now thought that CLA itself may not have anti-oxidant capabilities but may produce substances which protect cells from the detrimental effects of peroxides. There is, however, insufficient evidence from human epidemiological data, and very few of the animal studies have shown a dose-response relationship with the quantity of CLA feed and the extent of tumor growth. Further research with tumor models is needed to test the efficacy and utility of CLA in cancer and other disease prevention and form the basis of evaluating its effect in humans by observational studies and clinical trials.

Topics: Animals; Antioxidants; Arteriosclerosis; Dairy Products; Humans; Immunity; Linoleic Acid; Meat; Neoplasms

Conjugated linoleic acid (CLA) is a collective term for positional and geometric isomers of octadecadienoic acid in which the double bonds are conjugated, i.e. contiguous. CLA was identified as a component of milk and dairy products over 20 years ago. It is formed as an intermediate in the course of the conversion of linoleic acid to oleic acid in the rumen. The predominant naturally occurring isomer is the cis-9, trans-11 modification. Treatment of linoleic acid-rich oils such as safflower oil, soybean oil, or maize oil with base and heat will result in the formation of CLA. Two isomers predominate in the synthetic preparation, c9,t11 and t10,c12. CLA has been shown to inhibit chemically-induced skin, stomach, mammary or colon tumours in mice and rats. The inhibition of mammary tumours in rats is effective regardless of type of carcinogen or type or amount of dietary fat. CLA has also been shown to inhibit cholesterol-induced atherosclerosis in rabbits. When young animals (mice, pigs) are placed on CLA-containing diets after weaning they accumulate more body protein and less fat. Since CLA is derived from the milk of ruminant animals and is found primarily in their meat and in products derived from their milk there is a concerted world-wide effort to increase CLA content of milk by dietary means. Its effect on growth (less fat, more protein) is also a subject of active research. The mechanisms underlying the effects of CLA are still moot.

Topics: Animals; Antimutagenic Agents; Antineoplastic Agents; Arteriosclerosis; Body Composition; Colonic Neoplasms; Dairy Products; Female; Linoleic Acid; Mammary Neoplasms, Experimental; Mice; Milk; Rabbits; Rats; Skin Neoplasms

Conjugated linoleic acid (CLA) is being sold as a panacea that has the capability of reducing or eliminating cancer, preventing heart disease, improving immune function, and altering body composition to treat obesity or build lean body mass. Unfortunately, there has been very little published human research on CLA. This review will examine the literature on CLA and discuss the animal research on which the above claims are made. The limited human studies will be presented with an evaluation of the potential uses of CLA for human health and disease.

Topics: Adjuvants, Immunologic; Animals; Anticarcinogenic Agents; Arteriosclerosis; Body Composition; Humans; Linoleic Acid

Milk is often seen as a potential promotor of atherosclerosis and coronary heart disease because it is a source of cholesterol and saturated fatty acids. But there are several studies indicating that milk and milk products may not affect adversely blood lipids as would be predicted from its fat content and fat composition. There are even factors in milk and milk products which may actively protect from this condition by improving several risk factors. Calcium, bioactive peptides and as yet unidentified components in whole milk may protect from hypertension, and folic acid, vitamin B6 (pyridoxine) and B12 (cyanocobalamin) or other unidentified components of skim milk may contribute to low homocysteine levels. Conjugated linoleic acid may have hypolipidaemic and antioxidative and thus antiatherosclerotic properties. Epidemiological studies suggest that milk and milk products fit well into a healthy eating pattern emphasizing cereals and vegetables.

Topics: Animals; Anticholesteremic Agents; Antioxidants; Arteriosclerosis; Calcium; Cardiovascular Diseases; Coronary Disease; Diet; Humans; Hypertension; Linoleic Acid; Milk; Milk Proteins; Risk Factors; Vitamins

New results on the physiological properties of conjugated linoleic acid have been published by several working groups, especially showing the effects of single conjugated linoleic acid isomers on carcinogenesis and body composition. Recently, other studies have shown that conjugated linoleic acid has an influence on diabetes mellitus, platelet aggregation and the immune system. Conjugated linoleic acid was found to modify prostaglandin metabolism and delta9-desaturase activity and influence apoptosis. Furthermore, improved analytical methods using 13C nuclear magnetic resonance and silver ion high performance liquid chromatography are available to investigate the composition of conjugated linoleic acid mixtures and the exact structure of separated isomers. Also, the synthesis of isolated isomers is described, as published by different authors, in order to determine further the effects of each single conjugated linoleic acid isomer. In addition, new data on the contents of conjugated linoleic acid in foods, human adipose tissue and fluids are given in this review. More data need to be obtained using isolated isomers, with particular emphasis on studies in humans.

Topics: Adipose Tissue; Animals; Arteriosclerosis; Body Composition; Food Analysis; Humans; Linoleic Acid; Neoplasms

There is evidence that linoleic acid plays a critical role in gene expression and vascular function as it relates to the pathogenesis of atherosclerosis. The lipid environment, particularly linoleic acid and its derivatives, of the vascular endothelium may profoundly influence the inflammatory response mediated by cytokines. Modulations in the level of activity of a select set of endothelial transcription factors appear to provide a mechanism for linking lipid/cytokine-mediated vessel wall dysfunction, including endothelial cell activation, altered proteoglycan metabolism, and endothelial barrier dysfunction, with the onset of atherosclerotic lesion formation. The activity of endothelial transcription factors is in part regulated by the balance of cellular oxidative stress and antioxidant status. Our data suggest that linoleic acid can activate the vascular endothelium and may thus be an atherogenic fatty acid. Furthermore, nutrients/chemicals with antioxidant properties can protect endothelial cells against lipid-mediated cell injury, suggesting that oxidative stress is a critical component in linoleic acid-mediated gene expression. Our discoveries that linoleic acid can influence significantly the cytokine-mediated inflammatory response may open new fields in dietary intervention of atherosclerosis.

Topics: Animals; Arteriosclerosis; Cytokines; Endothelium, Vascular; Fatty Acids; Gene Expression; Humans; Linoleic Acid; NF-kappa B; Oxidation-Reduction; Proteoglycans; Signal Transduction

Dietary experiments, performed in metabolic wards, gave rise to predictive regression equations relating changes of plasma cholesterol concentration to the intake of fatty acids of the diet. It has been established that polyunsaturated fatty acids diminish and most saturated fatty acids increase plasma cholesterol concentration. This information led to expect that dietary use of palm oil may induce an unfavorable plasma lipoprotein profile. This has not been the case as shown in various dietary experiments. The reasons for this discrepancy is discussed. The influence of palm oil enriched diets on prothrombotic variables show that platelets are not affected in their function during prolonged dietary intervention. It is important to continue research on the effects of palm oil based diet on plasma fibrinogen, factor VII. There is still discordant information in this field.

Topics: Adult; Animals; Arteriosclerosis; Child; Cholesterol; Diet, Atherogenic; Dietary Fats; Factor VII; Feeding Behavior; Female; Fibrinogen; Fish Oils; Humans; Hypercholesterolemia; Linoleic Acid; Linoleic Acids; Lipoproteins; Male; Palm Oil; Plant Oils; Platelet Aggregation; Rabbits; Rural Population; Sunflower Oil; Thrombosis; Triglycerides; Urban Population; Venezuela

Oxidative reactions have been implicated in the development of numerous diseases including atherosclerosis and cancer. Oxidation of lipids, proteins, and nucleic acids can result in loss of membrane integrity and function, inactivation of enzymes, modification of lipoproteins, and chemical alteration of DNA. Active oxygen species, transition metals, reducing agents, and enzymes such as lipoxygenase are all involved in the catalysis of oxidative reactions. Since lipid oxidation catalysts and active oxygen species are ubiquitous to all biological systems and since lipid oxidation products can enter the body via oxidized foods, numerous endogenous antioxidant systems have been developed. Endogenous antioxidant systems include antioxidant enzymes, free radical scavengers, and metal chelators. The purpose of this review is to examine the potential of nonessential dietary components that inhibit oxidative reactions in foods and biological tissues.

Topics: Animals; Antioxidants; Arteriosclerosis; Carnosine; Diet; Humans; Linoleic Acid; Linoleic Acids; Neoplasms; Phenols; PQQ Cofactor; Quinolones

Topics: Adult; Arteriosclerosis; Cholesterol, Dietary; Coronary Disease; Diet, Atherogenic; Diet, Vegetarian; Dietary Carbohydrates; Dietary Fats; Eicosanoids; Energy Intake; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Feeding Behavior; Female; Humans; Hyperlipidemias; Incidence; Linoleic Acid; Linoleic Acids; Lipids; Lipoproteins; Male; Middle Aged; Molecular Structure; Obesity; Prevalence; Risk Factors

Topics: alpha-Linolenic Acid; Animals; Arteriosclerosis; Blood Platelets; Diabetes Complications; Dietary Fats; Fatty Acids; Fatty Acids, Unsaturated; Humans; Hyperlipoproteinemias; Linoleic Acid; Linoleic Acids; Linolenic Acids; Nutritional Physiological Phenomena; Thrombosis

Topics: Adolescent; Arteriosclerosis; Blood Pressure; Child; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diet, Sodium-Restricted; Dietary Fats; Energy Intake; Female; Humans; Hypertension; Linoleic Acid; Linoleic Acids; Lipoproteins; Male; Sodium

Topics: Arteriosclerosis; Blood Glucose; Carbohydrate Metabolism; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Glucose Tolerance Test; Humans; Intestinal Absorption; Linoleic Acid; Linoleic Acids; Lipids

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Dietary Fats; Eicosanoic Acids; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Linoleic Acids; Linolenic Acids; Platelet Aggregation; Prostaglandins; Thrombin; Thrombosis

To investigate the effects of increased alpha-linolenic acid (ALA)-intake on intima-media thickness (IMT), oxidized low-density lipoprotein (LDL) antibodies, soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and interleukins 6 and 10.. Randomized double-blind placebo-controlled trial.. Moderately hypercholesterolaemic men and women (55 +/- 10 y) with two other cardiovascular risk factors (n = 103).. Participants were assigned to a margarine enriched with ALA (fatty acid composition 46% LA, 15% ALA) or linoleic acid (LA) (58% LA, 0.3% ALA) for 2 y.. Dietary ALA intake was 2.3 en% among ALA users, and 0.4 en% among LA users. The 2-y progression rate of the mean carotid IMT (ALA and LA: +0.05 mm) and femoral IMT (ALA:+0.05 mm; LA:+0.04 mm) was similar, when adjusted for confounding variables. After 1 and 2 y, ALA users had a lower CRP level than LA users (net differences -0.53 and -0.56 mg/l, respectively, P < 0.05). No significant effects were observed in oxidized LDL antibodies, and levels of sICAM-1, interleukins 6 and 10.. A six-fold increased ALA intake lowers CRP, when compared to a control diet high in LA. The present study found no effects on markers for atherosclerosis.. The Dutch 'Praeventiefonds'.

Topics: Adult; Aged; alpha-Linolenic Acid; Arteriosclerosis; C-Reactive Protein; Dietary Fats; Double-Blind Method; Female; Humans; Hypercholesterolemia; Interleukin-10; Interleukin-6; Linoleic Acid; Male; Margarine; Middle Aged; Risk Factors

Although replacement of dietary saturated fat with monounsaturated and polyunsaturated fatty acids (MUFA and PUFA) has been advocated for the reduction of cardiovascular disease risk, diets high in PUFA could increase low density lipoprotein (LDL) susceptibility to oxidation, potentially contributing to the pathology of atherosclerosis. To investigate this possibility, 15 postmenopausal women in a blinded crossover trial consumed 15 g of sunflower oil (SU) providing 12.3 g/day of oleate, safflower oil (SA) providing 10.5 g/day of linoleate, and fish oil (FO) providing 2.0 g/day of eicosapentaenoate (EPA) and 1.4 g/day of docosahexaenoate (DHA). During CuSO(4)-mediated oxidation, LDL was depleted of alpha-tocopherol more rapidly after FO supplementation than after supplementation with SU (P = 0.0001) and SA (P = 0.05). In LDL phospholipid and cholesteryl ester fractions, loss of n-3 PUFA was greater and loss of n-6 PUFA less after FO supplementation than after SU and SA supplementation (P < 0.05 for all), but loss of total PUFA did not differ. The lag phase for phosphatidylcholine hydroperoxide (PCOOH) formation was shorter after FO supplementation than after supplementation with SU (P = 0.0001) and SA (P = 0.006), whereas the lag phase for cholesteryl linoleate hydroperoxide (CE18:2OOH) formation was shorter after FO supplementation than after SU (P = 0.03) but not SA. In contrast, maximal rates of PCOOH and CE18:2OOH formation were lower after FO supplementation than after SA (P = 0.02 and 0.0001, respectively) and maximal concentrations of PCOOH and CE18:2OOH were lower after FO supplementation than after SA (P = 0.03 and 0.0006, respectively). Taken together, our results suggest that FO supplementation does not increase the overall oxidation of LDL ex vivo, especially when compared with SA supplementation. Consequently, health benefits related to increased fish consumption may not be offset by increased LDL oxidative susceptibility.-- Higdon, J. V., S. H. Du, Y. S. Lee, T. Wu, and R. C. Wander. Supplementation of postmenopausal women with fish oil does not increase overall oxidation of LDL ex vivo compared to dietary oils rich in oleate and linoleate. J. Lipid Res. 2001. 42: 407--418.

Topics: Aged; Arteriosclerosis; Body Mass Index; Cholesterol Esters; Cross-Over Studies; Dietary Fats; Dietary Fats, Unsaturated; Docosahexaenoic Acids; Eicosapentaenoic Acid; Energy Intake; Estrogen Replacement Therapy; Fatty Acids, Unsaturated; Female; Fish Oils; Humans; Hydrogen Peroxide; Linoleic Acid; Lipoproteins, LDL; Middle Aged; Oleic Acid; Oxidation-Reduction; Plant Oils; Postmenopause; Sunflower Oil; Triglycerides; Vitamin E

We evaluated whether replacing a proportion of saturated fat with vegetable oils in the diet of young children increases trans fatty acid intake.. Dietary counseling aimed to reach a dietary fat ratio of unsaturated to saturated fat of 2:1 within a total fat intake of 30% to 35% of energy (E%). Four-day food records of 813 3-year-old children were analyzed, and serum phospholipid fatty acid compositions of 25 randomly selected intervention children and 17 control children were analyzed.. trans fatty acid intake of the intervention and control children was small (0.8 E% and 0.6 E%, respectively; P <.001). The relative content of serum phospholipid trans 18:1 was closely similar in intervention and control children (1.0% and 0.9% of all fatty acids, respectively). Trans fatty acid intake and serum trans 18:1 correlated poorly with children's serum cholesterol and HDL cholesterol concentrations and inversely with serum phospholipid arachidonic to linoleic acid ratio (r = -0.373).. Trans fatty acid intake of children in Finland is minimal. Dietary intervention replacing saturated with unsaturated fatty acids is safe because it does not increase trans fatty acid intake or the relative content of trans fatty acids in the serum phospholipid fraction.

Topics: Arachidonic Acid; Arteriosclerosis; Child, Preschool; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Counseling; Diet, Fat-Restricted; Dietary Fats; Dietary Fats, Unsaturated; Energy Intake; Fatty Acids; Fatty Acids, Unsaturated; Finland; Humans; Isomerism; Linoleic Acid; Medical Records; Phospholipids; Plant Oils; Prospective Studies; Risk Factors

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

Increased oxidative stress in vascular cells plays a key role in the development of endothelial dysfunction and atherosclerosis. Uncoupling protein 2 (UCP2) is an important regulator of intracellular reactive oxygen species (ROS) production. This study was undertaken to test the hypothesis that, UCP2 functions as an inhibitor of the atherosclerotic process in endothelial cells. Adenovirus-mediated UCP2 (Ad-UCP2) overexpression led to a significant increase in endothelial nitric oxide synthase (eNOS) and decrease in endothelin-1 mRNA expression in human aortic endothelial cells (HAECs). Moreover, UCP2 inhibited the increase in ROS production and NF-kappaB activation, and apoptosis of HAECs induced by lysophophatidylcholine (LPC) and linoleic acid. LPC and linoleic acid caused mitochondrial calcium accumulation and transient mitochondrial membrane hyperpolarization, which was followed by depolarization. UCP2 overexpression prevented these processes. In isolated rat aorta, Ad-UCP2 infection markedly improved impaired vascular relaxation induced by LPC. The data collectively suggest that UCP2, functions as a physiologic regulator of ROS generation in endothelial cells. Thus, measures to increase UCP2 expression in vascular endothelial cells may aid in preventing the development and progression of atherosclerosis in patients with metabolic syndrome.

Topics: Adenoviridae; Apoptosis; Arteriosclerosis; Calcium; Caspases; Cells, Cultured; Electron Transport; Endothelial Cells; Endothelin-1; Gene Transfer, Horizontal; Humans; Ion Channels; Linoleic Acid; Lysophosphatidylcholines; Membrane Transport Proteins; Mitochondrial Proteins; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Reactive Oxygen Species; RNA, Messenger; Uncoupling Protein 2

The linoleic C18:2 (n-6) and linolenic C18:3 (n-3) are recognized as essential components of the diet. Free radical peroxidation of essential fatty acids (EFAs) present in lipoproteins produces oxidized low-density lipoproteins which play a critical role in the development of atherosclerosis. The accumulation of EFAs in the vascular wall and correlations between their content in the adipose tissue and atherosclerotic plaque have been confirmed. The present study was undertaken to determine the usefulness of a neural network for studying the exchange between tissues of linoleic, alpha-linolenic, and arachidonic acids-three fatty acids with a well-understood metabolism. Atheromatous plaques, adipose tissue, and serum were obtained from 31 patients who underwent surgery due to atherosclerotic stenosis of the abdominal aorta, iliac or femoral arteries. Fatty acids were extracted and separated as methyl esters using gas chromatography. Statistical analysis was done with STATISTICA neural networks package. Several correlations reported previously were corroborated and factors modifying the content of individual EFAs in adipose tissue and atherosclerotic plaque were revealed. Artificial neural networks (ANNs) were used to determine factors modifying the content of linoleic, alpha-linolenic, and arachidonic acids in human atheromatous plaques. The mechanism of exchange of some fatty acids between the adipose tissue, atheromatous plaque, and plasma is discussed. The results provide evidence for an effective mechanism of tissue uptake and turnover of linoleic acid. Reduced plasma levels of this acid are compensated by release from adipose tissue and atheromatous plaque. While alpha-linolenic acid is continuously taken up by the plaque, adipose tissue absorbs this acid to a certain level only. The dynamics of exchange of arachidonic acid between adipose tissue and atheromatous plaque reflects a minor role for adipose tissue in determining plaque content of this acid, suggesting that "de novo" synthesis is the chief source of arachidonic acid in plaques.

Topics: Adipose Tissue; Aged; Arteriosclerosis; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Male; Middle Aged; Neural Networks, Computer; White People

Macrophage cholesterol homeostasis is a key process involved in the initiation and progression of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) regulate the transcription of the genes involved in cholesterol homeostasis and thus represent an important therapeutic target in terms of reducing atherosclerosis. Conjugated linoleic acid (CLA) is a potent anti-atherogenic dietary fatty acid in animal models of atherosclerosis and is capable of activating PPARs in vitro and in vivo. Therefore, this study examined whether the anti-atherogenic effects of CLA in vivo could be ascribed to altered cholesterol homeostasis in macrophages and macrophage derived foam cells. Of several genes that regulate cholesterol homeostasis investigated, CLA had most effect on the class B scavenger receptor CD36. The cis-9,trans-11 CLA (c9,t11-CLA) and trans-10,cis-12 CLA (t10,c12-CLA) isomers augmented CD36 mRNA expression (P<0.001). Confocal laser microscopy characterised the three-dimensional expression patterns of CD36 in THP-1 macrophages. Linoleic acid, CLA and the PPARgamma ligand rosiglitazone increased discrete cell surface CD36 localisation, with a heterogeneous punctate pattern of expression. In agreement with the observed increases in CD36 mRNA and cell surface expression, intracellular cholesterol concentrations were greater in macrophages exposed to linoleic acid and CLA. Further analysis of cholesterol metabolism showed that CLA had no effect on THP-1 derived foam cell cholesterol efflux to apo AI. Thus, altered cholesterol homeostasis in the macrophage may not explain the anti-atherogenic effects of CLA observed in vivo.

Topics: Analysis of Variance; Arteriosclerosis; Biomarkers; CD36 Antigens; Cells, Cultured; Cholesterol; Foam Cells; Homeostasis; Humans; Linoleic Acid; Macrophages; Microscopy, Confocal; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA; Sensitivity and Specificity

Currently, diets higher in polyunsaturated fat are believed to lower blood cholesterol concentrations, and thus reduce atherosclerosis, greater than diets containing high amounts of saturated or possibly even monounsaturated fat. The present study was designed to investigate the effect of diets containing mid- or high-linoleic oil versus the typical high-linoleic sunflower oil on LDL oxidation and the development of early atherosclerosis in a hypercholesterolemic hamster model. Animals were fed a hypercholesterolemic diet containing 10% mid-oleic sunflower oil, high-oleic olive oil, or high-linoleic sunflower oil (wt/wt) plus 0.4% cholesterol (wt/wt) for 10 weeks. After 10 weeks of dietary treatment, only the animals fed the mid-oleic sunflower oil had significant reductions in plasma LDL-C levels (-17%) compared to the high-linoleic sunflower oil group. The high-oleic olive oil-fed hamsters had significantly higher plasma triglyceride levels (+41%) compared to the high-linoleic sunflower oil-fed hamsters. The tocopherol levels in plasma LDL were significantly higher in hamsters fed the mid-oleic sunflower oil (+77%) compared to hamsters fed either the high-linoleic sunflower or high-oleic olive oil. Measurements of LDL oxidation parameters, indicated that hamsters fed the mid-oleic sunflower oil and high-oleic olive oil diets had significantly longer lag phase (+66% and +145%, respectively) and significantly lower propagation rates (-26% and -44%, respectively) and conjugated dienes formed (-17% and -25%, respectively) compared to the hamsters fed the high-linoleic sunflower oil. Relative to the high-linoleic sunflower oil, aortic cholesterol ester was reduced by -14% and -34% in the mid-oleic sunflower oil and high-oleic olive oil groups, respectively, with the latter reaching statistical significance. Although there were no significant associations between plasma lipids and lipoprotein cholesterol with aortic total cholesterol and cholesterol esters for any of the groups, the lag phase of conjugated diene formation was inversely associated with both aortic total and esterified cholesterol in the high-oleic olive oil-fed hamsters (r = -0.69, P < 0.05). The present study suggests that mid-oleic sunflower oil reduces risk factors such as lipoprotein cholesterol and oxidative stress associated with early atherosclerosis greater than the typical high-linoleic sunflower oil in hypercholesterolemic hamsters. The high-oleic olive oil not only significantly red

Topics: alpha-Tocopherol; Animals; Aorta; Aortic Diseases; Arteriosclerosis; Cholesterol Esters; Cholesterol, HDL; Cholesterol, LDL; Cricetinae; Hypercholesterolemia; Linoleic Acid; Lipids; Lipoproteins, LDL; Mesocricetus; Oleic Acid; Olive Oil; Plant Oils; Risk Factors; Sunflower Oil

Markers of lipid peroxidative damage have been shown to be elevated in individuals with risk factors for cardiovascular disease, and human atherosclerotic plaque contains products resulting from lipid peroxidation. In particular, the presence of fatty acid oxidation products such as hydroxyeicosatetraenoic acids (HETEs) has previously been suggested as a marker of plaque instability and symptomatic cerebrovascular disease. The aim of the present study was to quantitate the levels of various oxidation products of linoleic acid (HODEs) and arachidonic acid (HETEs), respectively, in human atherosclerotic plaque tissue and assess their level in relation to plaque histopathology, symptoms of cerebrovascular disease and preexisting atherosclerotic risk factors. We also assessed the correlation between the levels of the hydroxy fatty acid compounds and F(2)-isoprostanes, an established marker of in vivo free radical mediated oxidation. Hydroxy fatty acid oxidation products were identified in all histological subtypes of advanced plaque. However, there were no significant differences in levels between the histopathologically classified sub-groups or between patients symptomatic or asymptomatic for cerebrovascular disease. Arachidonic acid oxidation products were significantly higher in those subjects who also had symptomatic peripheral vascular disease. The level of linoleic acid oxidation products was significantly higher in individuals who consumed alcohol on a regular basis. While F(2)-isoprostanes and fatty acid oxidation products were highly correlated (P<0.01), levels of the hydroxy fatty acid compounds were 20-40-fold higher than F(2)-isoprostanes. Chiral analysis of the plaque extracts indicated that all HODEs and HETEs originated primarily from non-enzymatic lipid peroxidation. While our results do not support previous reports that fatty acid oxidation products such as the HETEs are associated with plaque instability and symptomatic cerebrovascular disease, further work is warranted to determine the potential of these compounds as circulating markers for underlying atherosclerotic disease and lipid peroxidative stress.

Topics: Aged; Arachidonic Acid; Arteriosclerosis; Carotid Artery Diseases; Culture Techniques; Endarterectomy, Carotid; Fatty Acids; Female; Gas Chromatography-Mass Spectrometry; Humans; Immunohistochemistry; Isoprostanes; Linoleic Acid; Lipid Peroxidation; Male; Probability; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of antioxidants, 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols, to overcome the clinical limitation of vitamin E. In vitro, the compounds showed a potent inhibitory effect on lipid peroxidation detected as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA)-dependent chemiluminescence in linoleic acid autoxidation. They also inhibited the LDL oxidation induced by Cu(2+), and the inhibition is more potent than that of vitamin E and probucol. In vivo, 4,6-di-tert-butyl-2,3-dihydro-2,2-dipentyl-5-benzofuranol (BO-653, 1f), an optimal compound, showed the highest concentration in plasma and LDL fraction in Watanabe heritable hyperlipidemic rabbits, due to its high affinity to LDL. The isolated LDL samples from the 1f-treated rabbits showed potent resistibility to LDL oxidation. Compound 1f has been taken into clinical trials.

Topics: alpha-Tocopherol; Animals; Antioxidants; Arteriosclerosis; Benzofurans; Free Radicals; Linoleic Acid; Lipoproteins, LDL; Luminescent Measurements; Oxidation-Reduction; Rabbits; Structure-Activity Relationship

To develop a method to preserve lipids in formalin-fixed tissues for staining in paraffin sections, and to illustrate its use in lung and brain of a fat embolism case, and in examples of fatty liver and atheroma.. A saturated solution of linoleic acid in 70% ethylene glycol was prepared and tissues were exposed to this for 3 days at 56 degrees C. These tissues were treated with 2% chromic acid at 4 degrees C for 24 h followed by 24 h in 5% sodium bicarbonate, with appropriate rinsing between solutions. Paraffin sections of these tissues were stained with a lipid-soluble dye such as Oil Red O. Examples of fat embolism, fatty liver, and atheroma were shown photographically as illustrations of expected results.. The demonstration of fat embolism with good quality tissue detail is made practical by the method, which is convenient and inexpensive. The method appears to be generally applicable to tissue lipids of various sorts, as exemplified by adipose tissue, fatty liver, and atheroma.

Topics: Adipocytes; Arteriosclerosis; Azo Compounds; Brain; Chromates; Embolism, Fat; Ethylene Glycol; Fatty Liver; Humans; Linoleic Acid; Lipids; Lung; Microscopy, Electron; Myocytes, Smooth Muscle; Paraffin Embedding; Sodium Bicarbonate; Tissue Fixation

Lipid peroxidation (LPO) processes observed in diseases connected with inflammation involve mainly linoleic acid. Its primary LPO products, 9-hydroperoxy-10,12-octadecadienoic acid (9-HPODE) and 13-hydroperoxy-9,11-octadecadienoic acid (13-HPODE), decompose in multistep degradation reactions. These reactions were investigated in model studies: decomposition of either 9-HPODE or 13-HPODE by Fe(2+) catalyzed air oxidation generates (with the exception of corresponding hydroxy and oxo derivatives) identical products in often nearly equal amounts, pointing to a common intermediate. Pairs of carbonyl compounds were recognized by reacting the oxidation mixtures with pentafluorobenzylhydroxylamine. Even if a pure lipid hydroperoxide is subjected to decomposition a great variety of products is generated, since primary products suffer further transformations. Therefore pure primarily decomposition products of HPODEs were exposed to stirring in air with or without addition of iron ions. Thus we observed that primary products containing the structural element R-CH=CH-CH=CH-CH=O add water and then they are cleaved by retroaldol reactions. 2,4-Decadienal is degraded in the absence of iron ions to 2-butenal, hexanal and 5-oxodecanal. Small amounts of buten-1,4-dial were also detected. Addition of m-chloroperbenzoic acid transforms 2,4-decadienal to 4-hydroxy-2-nonenal. 4,5-Epoxy-2-decenal, synthetically available by treatment of 2,4-decadienal with dimethyldioxirane, is hydrolyzed to 4,5-dihydroxy-2-decenal.

Topics: Air; Aldehydes; Arteriosclerosis; Cations, Divalent; Chromatography, High Pressure Liquid; Epoxy Compounds; Gas Chromatography-Mass Spectrometry; Humans; Hydroxylamines; Iron; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Lipid Peroxides; Lipoxygenase; Magnetic Resonance Spectroscopy; Models, Chemical; Molecular Structure; Oxidation-Reduction

Multifactorial interaction among lipoproteins, vascular wall cells, and inflammatory mediators has been recognized as the basis of atherogenesis. In the arterial wall high-density lipoprotein (HDL) and human secretory phospholipase A(2) (sPLA(2)) colocalize with vascular smooth muscle cells and concentrate in the atherosclerotic lesions. It has been shown that gr IIA sPLA(2) hydrolyzes lipoproteins, altering their structure and releasing active agents such as lyso-phosphatidylcholine (PtdCho) and free fatty acids. We investigated the impact of normal HDL(3) (NHDL(3)), acute phase HDL(3) (APHDL(3)), and low-density lipoprotein (LDL), both unhydrolyzed and sPLA(2)-hydrolyzed, and some products of hydrolysis, such as lyso-PtdCho, oleic and linoleic acid, on [(3)H] thymidine incorporation by DNA of cultured human vascular smooth muscle cells (VSMC). NHDL(3) markedly enhanced mitogenic activity of VSMC in a dose- and time-dependent manner. Doubling of thymidine incorporation was usually achieved by 40 microg/ml of NHDL(3) after 4 hours of incubation. APHDL(3) had invariably a stronger inducing effect on the mitogenic activity than NHDL(3); 40 microg/ml more than tripled [(3)H] thymidine incorporation after 4 hours of incubation. NHDL(3) preincubated with human apo serum amyloid A apolipoprotein-induced higher mitogenic activity in VSMC than NHDL(3) alone. Hydrolysis of NHDL(3), APHDL(3), or LDL by gr IIA sPLA(2) markedly enhanced mitogenic activity of VSMC as compared with unhydrolyzed lipoproteins. sPLA(2) concentrations that can be found in atherosclerotic vascular walls markedly enhanced lipoprotein-induced mitogenic activity of VSMC. sPLA(2) per se did not affect thymidine incorporation and VSMC did not release sPLA(2) into the medium. There was no evidence for hydrolysis of the wall of VSMC by gr IIA sPLA(2). The presence of the products of hydrolysis of lipoproteins such as oleic and linoleic acids and lyso-PtdCho or their combinations with NHDL(3) explains in part markedly enhanced mitogenic activity of VSMC. It is conceivable that sPLA(2,) which is known to colocalize with lipoproteins in the vascular wall in the domain of VSMC, is capable of induction of the mitogenic activity in these cells in vivo and should be considered as a proatherogenic enzyme.

Topics: Acute-Phase Proteins; Arteriosclerosis; Cell Division; Cells, Cultured; Humans; Hydrolysis; Linoleic Acid; Lipoproteins; Lipoproteins, HDL; Lysophosphatidylcholines; Mitogens; Muscle, Smooth, Vascular; Oleic Acid; Phospholipases A

Nonhuman primates used in these studies had been fed for 5 years diets enriched with cholesterol and one of three classes of fatty acids: saturated, monounsaturated, or polyunsaturated fatty acids. Atherosclerotic iliac artery lipid extracts were quantitatively analyzed for cholesterol, cholesteryl esters, fatty acid composition, and a marker of lipid oxidation, the F(2)-isoprostanes. There was no significant difference in the mean accumulation of F(2)-isoprostanes among the different diet groups. To account for the small, individual variation in the arachidonate concentration the F(2)-isoprostane mass from each sample was normalized by dividing by arachidonate mass: F(2)-isoprostane mass/(mass arachidonate). At lower levels of cholesterol accumulation, the F(2)-isoprostane mass/(mass arachidonate) ratio was greater in lipids from POLY arteries compared to SAT arteries, but the reverse was true at high levels of cholesterol. F(2)-isoprostane/(mass arachidonate) increased with mole fraction linoleate for the SAT group, but decreased for the POLY group. In summary, these studies demonstrated that there is no simple explanation of how F(2)-isoprostane accumulation did not depend on the concentration of oxidizable lipids that promote free-radical lipid oxidation.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Chlorocebus aethiops; Cholesterol; Cholesterol Esters; Cholesterol, LDL; Diet, Atherogenic; Dietary Fats; Dinoprost; Fatty Acids; Free Radicals; Iliac Artery; Linoleic Acid; Lipid Peroxidation; Lipids; Oleic Acid; Oxidation-Reduction; Palm Oil; Plant Oils; Safflower Oil

Maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in human fetuses and faster progression of atherosclerosis during childhood even under normocholesterolemic conditions. A causal role of maternal hypercholesterolemia in lesion formation during fetal development has previously been established in rabbits. The same experimental model is now used to establish that maternal hypercholesterolemia or ensuing pathogenic events in fetal arteries enhance atherogenesis later in life. Five groups of rabbit mothers were fed chow, cholesterol-enriched chow, or cholesterol-enriched chow plus 1000 IU vitamin E, 3% cholestyramine, or both during pregnancy. Offspring of all groups (n=136) were fed a mildly hypercholesterolemic diet for up to a year and had similar cholesterol levels. Aortic lesion sizes and lipid peroxidation products in plasma and lesions in offspring were determined at birth, 6 months, or 12 months. Lesion progression in offspring of hypercholesterolemic mothers was greater than in all other groups. At each time point, offspring of hypercholesterolemic mothers had 1.5- to 3-fold larger lesions than offspring of normocholesterolemic mothers (P<0.01), with the greatest absolute differences at 12 months. Maternal treatment reduced lesions by 19% to 53%, compared with offspring of untreated hypercholesterolemic mothers (P<0.01), with the greatest effect in the vitamin E groups. At 12 months, lesions in offspring of all vitamin E and cholestyramine-treated mothers were similar to those of normocholesterolemic mothers. Lipid peroxidation end-products in lesions and plasma showed analogous differences between groups as lesions (P<0.01). Thus, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering drugs or antioxidants reduce postnatal lipid peroxidation and atherosclerosis in their offspring.

Topics: Animals; Anticholesteremic Agents; Antioxidants; Aorta; Aortic Diseases; Arteriosclerosis; Cholestyramine Resin; Disease Progression; Female; Hypercholesterolemia; Linoleic Acid; Lipid Peroxidation; Malondialdehyde; Pregnancy; Rabbits; Vitamin E

Atherosclerosis is increasingly recognized as an inflammatory disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine, recently implicated as a prominent component of the regulatory network involved in atherogenesis. We aimed to study the relationship between circulating GM-CSF levels and serum fatty acid (FA) composition in 78 healthy subjects. The latter was analyzed by gas-liquid chromatography and GM-CSF by a high-sensitivity commercial enzyme-linked immunosorbent assay (ELISA). Among women (n = 40), serum GM-CSF levels were found to be positively associated with the proportion of palmitic acid (C16:0) and negatively with linoleic acid (C18:2omega-6), docosahexaenoic acid (DHA, C22:6omega-3), and the proportion of total essential FA. After excluding smoking women (n = 6), the associations among GM-CSF and serum linoleic acid concentration (r = -0.49, P =.003), arachidonic acid (r = -0.52, P =.001), and DHA (r = -0.34, P =.04) were strengthened. The ratio of palmitic to linoleic and DHA acids was the single best predictor of serum GM-CSF in all subjects. Together with arachidonic acid, it contributed to 22% of the GM-CSF variance in women, after taking into account the effects of age, body mass index (BMI), blood pressure, and smoking status. None of these associations were observed among men. In conclusion, serum FA composition is associated with circulating GM-CSF specifically in women. As human arterial and venous smooth muscle cells release GM-CSF, and treatment of endothelial cells with oxidized low-density lipoproteins results in a rapid expression of GM-CSF, the mechanisms involved in these associations and the sex-linked differences should be further explored.

Topics: Adult; Arteriosclerosis; Blood Pressure; Body Mass Index; Docosahexaenoic Acids; Enzyme-Linked Immunosorbent Assay; Fatty Acids; Fatty Acids, Unsaturated; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Linear Models; Linoleic Acid; Male; Middle Aged; Palmitic Acid; Reference Values; Sex Characteristics; Smoking

To determine effects of conjugated linoleic acid (CLA) on establishment and progression of experimentally-induced atherosclerosis in rabbits.. For establishment of atherosclerosis, New Zealand White rabbits were fed a semipurified diet containing 0.1% to 0.2% cholesterol for 90 days. Some groups were fed diet and CLA. For effects on progression of atherosclerosis, rabbits with established atherosclerosis were fed a semipurified diet +/- CLA for 90 days.. At dietary levels as low as 0.1%, CLA inhibited atherogenesis. At dietary levels of 1%, CLA caused substantial (30%) regression of established atherosclerosis. This is the first example of substantial regression of atherosclerosis being caused by diet alone.. Dietary CLA is an effective inhibitor of atherogenesis and also causes regression of established atherosclerosis.

Topics: Animals; Aorta; Arteriosclerosis; Dietary Fats, Unsaturated; Female; Linoleic Acid; Lipids; Liver; Male; Rabbits

The CCR2-mediated recruitment of monocytes into the vessel wall plays an important role in all stages of atherosclerosis. In recent studies, we have shown that lipoproteins can modulate CCR2 expression and have identified native LDL as a positive regulator. In contrast, oxidized LDL (OxLDL), which is mainly formed in the aortic intima, reduces CCR2 expression, promotes monocyte retention, and may cause pathological accumulation of monocytes in the vessel wall. We now provide evidence that OxLDL reduces monocyte CCR2 expression by activating intracellular signaling pathways that may involve peroxisome proliferator-activated receptor gamma (PPARgamma). Receptor-mediated uptake of the lipoprotein particle was required and allows for delivery of the exogenous ligand to the nuclear receptor. The suppression of CCR2 expression by OxLDL was mediated by lipid components of OxLDL, such as the oxidized linoleic acid metabolites 9-HODE and 13-HODE, known activators of PPARgamma. Modified apoB had no such effect. Consistent with a participation of the PPARgamma signaling pathway, BRL49653 reduced CCR2 expression in freshly isolated human monocytes ex vivo and in circulating mouse monocytes in vivo. These results implicate PPARgamma in the inhibition of CCR2 gene expression by oxidized lipids, which may help retain monocytes at sites of inflammation, such as the atherosclerotic lesion.

Topics: Animals; Apolipoproteins B; Arteriosclerosis; Cells, Cultured; Down-Regulation; Humans; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Lipoproteins, LDL; Mice; Monocytes; Muscle, Smooth, Vascular; Phospholipids; Receptors, CCR2; Receptors, Chemokine; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Rosiglitazone; Signal Transduction; Thiazoles; Thiazolidinediones; Transcription Factors

Topics: Animals; Arteriosclerosis; Diet; Disease Models, Animal; Humans; Linoleic Acid; Lipids

Topics: Adult; Aged; Aged, 80 and over; Aging; Arteriosclerosis; Arthritis, Rheumatoid; Humans; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Lipid Peroxidation; Lipoproteins, LDL; Middle Aged

The current study was designed to investigate the hypocholesterolemic and anti-atherogenic properties of soy lecithin beyond its fatty acid content. In experiment 1, 18 cynomolgus monkeys were divided into three groups of six and fed diets which approximated either the average American diet (AAD), the American Heart Association (AHA) Step I diet, or a modified AHA (mAHA) Step I diet containing 3.4% soy lecithin for 8 weeks. Plasma samples were collected from food-deprived monkeys and analyzed for total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), very low- and low-density lipoprotein cholesterol (non-HDL-C), and triglyceride (TG) concentrations. Group comparisons revealed that monkeys fed the mAHA Step 1 diet had significantly lower plasma TC (-46%) and non-HDL-C (-55%) levels compared to the AAD diet, whereas monkeys fed the AHA Step 1 diet had lesser reductions in plasma TC (-21%) and non-HDL-C (-18%) levels. The monkeys fed the mAHA Step I diet had significantly lower plasma TC (-32%) and non-HDL-C (-45%) compared to the monkeys fed the AHA step diet. Also, only the mAHA Step I diet significantly reduced pre-treatment plasma TC and non-HDL-C levels by - 39 and -51% respectively with no significant effect on plasma HDL-C or TG levels. In experiment 2, 45 hamsters were divided into three groups of 15 and fed the following three modified non-purified diets for 8 weeks: a hypercholesterolemic diet (HCD) containing 10%, coconut oil and 0.05%, cholesterol, HCD plus 3.4%, soy lecithin (+SL), or the HCD with added levels of linoleate and choline equivalent to the +SL diet but no lecithin (-SL). Plasma lipids were determined as in experiment 1 and aortas were perfusion-fixed and Oil Red O stained for morphometric analyses of fatty streak area. Relative to the HCD group, the +SL-treated hamsters had significantly lower plasma TC (-58%), non-HDL-C (-73%) and aortic fatty streak area (-90%). Relative to the -SL group, hamsters fed the +SL diet had significantly lower plasma TC (-33%), non-HDL-C (-50%) and significantly reduced aortic fatty streak area (-79%). In conclusion, the first experiment suggests that the cholesterol-lowering efficacy of the AHA Step I diet can be enhanced with the addition of soy lecithin without reducing plasma HDL-C levels. whereas the second experiment suggest that the hypocholesterolemic, and in particular, the anti-atherogenic properties of soy lecithin cannot be attributed solely to its linoleate content.

Topics: Animals; Arteriosclerosis; Cholesterol; Cricetinae; Dietary Fats; Dietary Supplements; Hypercholesterolemia; Linoleic Acid; Macaca fascicularis; Male; Phosphatidylcholines; Soybean Oil

The three major cell types of the human atherosclerotic lesion--macrophages (Mø), smooth muscle cells (SMC) and endothelial cells (EC)--were compared for their ability to oxidise low density lipoprotein (LDL) in vitro under identical conditions. Near-confluent cultures were incubated for up to 48 h with 50 microg protein/ml LDL in Ham's F10 medium supplemented with 7 microM Fe2+. All three cell types oxidised LDL readily using our culture conditions. After 24 and 48 h, the degree of LDL oxidation was in the order: Mø > SMC > EC when based on cell growth area and EC > SMC > Mo when based on cellular DNA content. However, LDL oxidation in vitro progressed more slowly between 24 and 48 h, probably due to increasing toxicity to the cells and/or depletion of polyunsaturated fatty acids. We therefore compared the time of onset of LDL oxidation. The earliest increase in LDL oxidation was always apparent with SMC. Gas chromatography revealed that LDL oxidation by all three cell types followed a similar pattern. The polyunsaturated fatty acids linoleic acid (18:2) and arachidonic acid (20:4) were depleted (to 10.3-18.1% and 4.5-24.7% respectively, compared to native LDL), whereas the content of stearic acid (18:0) and oleic acid (18:1) remained unchanged. Cholesterol was depleted (to 54.1-75.6% of native LDL) with a concomitant rise in 7 -hydroxycholesterol (to 60.6-128.1 microg/mg LDL). This corresponds to a conversion of 4.9, 9.5 and 10.4% of LDL cholesterol in EC-, SMC- and Mo-modified LDL respectively. All three cell types showed significant toxicity in the oxidising culture after 24h. The possible relevance to LDL oxidation in atherosclerosis is discussed.

Topics: Aorta; Arachidonic Acid; Arteriosclerosis; Cells, Cultured; Cholesterol; Chromatography, Gas; Culture Media; Electrophoresis, Agar Gel; Endothelium, Vascular; Humans; Linoleic Acid; Lipid Peroxidation; Lipoproteins, LDL; Macrophages; Muscle, Smooth, Vascular; Oleic Acid; Oxidation-Reduction; Stearic Acids; Thiobarbituric Acid Reactive Substances

Oxidative modification of low density lipoprotein has been suggested as patho-physiologically relevant process in atherogenesis and the lipid peroxidizing enzyme 15-lipoxygenase may be involved. For experimental evidence on the in vivo action of this enzyme in the time course of plaque formation we analyzed the lipid extracts of lesional areas representing various stages of human atherogenesis for the occurrence of specific 15-lipoxygenase products. In advanced human lesions the degree of oxygenation of the lesion lipids measured as hydroxy linoleic acid/linoleic acid ratio varied between 0.2 and 3.2%. Here an unspecific pattern of oxygenated lipids that did not differ from the pattern formed during copper-catalyzed LDL oxidation was detected. In both cases an enantiomer ratio (S/R-ratio) of 13-hydroxy-9Z,11E-octadecadienoic acid (13-HODE) of approximately 1:1 was found. In young human lesions which were obtained from the collection of the pathological determinants of atherosclerosis in youth (PDAY) program the hydroxy linoleic acid/linoleic acid ratio was much smaller (variation between 0.05 and 0.6%), and a significant share of specific 15-lipoxygenase products was detected (S/R-ratio of 13-hydroxy linoleic acid of 54 +/- 3.1/46 +/- 3.1 [mean +/- SD]). These data suggest that the 15-lipoxygenase is enzymatically active on endogenous substrates in young human lesions and thus, may be of patho-physiological importance for early atherogenesis. In advanced human plaques the 15-lipoxygenase may be functionally silent and specific lipoxygenase products formed in earlier stages may be decomposed or superimposed by large amounts of nonenzymatic lipid peroxidation products.

Topics: Adolescent; Adult; Age Factors; Aged; Arachidonate 15-Lipoxygenase; Arteriosclerosis; Cholesterol, LDL; Chromatography, High Pressure Liquid; Copper; Fatty Acids; Female; Humans; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction

Conjugated linoleic acid is a collective term used to designate a mixture of positional and geometric isomers of linoleic acid in which the double bonds are conjugated. Unlike linoleic acid, there is a paucity of information regarding the effect of dietary conjugated linoleic acid on plasma lipoproteins and aortic atherosclerosis. Therefore, fifty hamsters were divided into five groups of ten and fed 0 (Control), 0.06 (LOW), 0.11 (MEDIUM), and 1.1 (HIGH) en% conjugated linoleic acid or 1.1 en% linoleic acid. Blood samples were taken at 4, 8 and 11 weeks for plasma lipid analyses and for plasma tocopherol assay at sacrifice. Animals fed the conjugated linoleic acid-containing diets collectively had significantly reduced levels of plasma total cholesterol, non-high density lipoprotein cholesterol, (combined very low and low density lipoprotein) and triglycerides with no effect on high density lipoprotein cholesterol, as compared to CONTROLs. Linoleic acid-fed animals relative to CONTROLs also had reduced plasma total cholesterol, non-high density lipoprotein cholesterol and triglycerides, but only the latter was statistically significant. Compared to the CONTROL group, plasma tocopherol/total cholesterol ratios determined from plasma pools for the LOW, MEDIUM and HIGH conjugated linoleic acid and linoleic acid groups were increased by 48%, 48%, 86% and 29%, respectively, suggesting a tocopherol-sparing effect, at least for the conjugated linoleic acid treatment. Morphometric analysis of aortas revealed less early atherosclerosis in the conjugated linoleic acid and linoleic acid-fed hamsters compared to the CONTROL group.

Topics: Animals; Aortic Diseases; Arteriosclerosis; Cricetinae; Dietary Fats, Unsaturated; Hypercholesterolemia; Linoleic Acid; Linoleic Acids; Lipids; Lipoproteins; Male; Time Factors; Vitamin E

Oxidative modification of LDL is believed to play a major role in atherogenesis. As major lipid peroxidation products oxygenated linoleic acid derivatives and oxysterols have been described in human atherosclerotic lesions. Here we report that human lesions contain isoprostanes as peroxidation products of arachidonic acid at a level of 27.1 +/- 21.2 pg/mg wet weight (n = 10), which corresponds to 75.9 +/- 59.3 pg/mg dry weight, n contrast, human umbilical veins (n = 10), which were used as nonatherosclerotic control vessels, contain much smaller amounts of isoprostanes (1.4 +/- 0.7 pg/mg wet weight, which corresponds to 11.7 +/- 6.2 pg/mg dry weight), and there are significant differences between the two types of vessels. As major products of linoleic acid oxidation, racemic hydroxy linoleate isomers were detected in the lesional ester lipids. In human lesions, the hydroxy linoleic acid/linoleic acid ratio was about 0.5%, a result indicating that 5 out of 1000 linoleate residues are present as hydroxylated derivatives. In umbilical veins, no hydroxy linoleic acid could be detected. These data show that human atherosclerotic lesions contain increased amounts of hydroxy linoleic acid isomers and isoprostanes when compared with nonatherosclerotic vessel wall and suggest a link between local lipid peroxidation and progression of atherosclerosis. For evaluation of the degree of lipid peroxidation, the determination of the hydroxy linoleic acid/linoleic acid ratio appears to be more suitable than the isoprostane content.

Topics: Aged; Arachidonic Acid; Arteries; Arteriosclerosis; Chromatography, High Pressure Liquid; Dinoprost; Female; Humans; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Umbilical Veins

Free-radical oxidation of human plasma low-density lipoprotein (LDL) produces (carboxyalkyl)pyrrole (CAP) epitopes that were detected with enzyme-linked immunosorbent assays using antibodies raised against keyhole limpet hemocyanin (KLH)-bound 2-(omega-carboxyheptyl)-pyrrole (CHP) and 2-(omega-carboxypropyl)pyrrole (CPP). These antibodies exhibit high structural selectivity (< 0.5% cross-reactivity) in competitive binding inhibition assays with the corresponding human serum albumin (HSA)-bound pyrroles. No cross-reactivity was detected for HSA-bound 2-pentylpyrrole, an epitope that is generated by a reaction of 4-hydroxy-2-nonenal (HNE) with protein lysyl residues. Oxidation of either arachidonic or linoleic acid in the presence of HSA produced an HNE-derived 2-pentylpyrrole epitope. However, only oxidation of linoleic acid formed HSA-bound CHP, while only oxidation of arachidonic acid generated HSA-bound CPP. Since ester hydrolysis with KOH markedly elevated levels of immunoreactive epitopes detected in oxidized LDL, the CAPs are presumably generated by reactions of oxidized cholesteryl esters, triglycerides, and phospholipids with LDL protein, and only some of these oxidized esters are hydrolyzed, e.g., by phospholipase activity associated with LDL. Protein-bound CHP immunoreactivity was detected in human plasma, and levels are significantly elevated in renal failure and atherosclerosis patients compared with healthy volunteers. This provides the first evidence for the biological occurrence of protein-bound CAPs in vivo and further suggests that free-radical oxidation of polyunsaturated lipids produces hydroxyalkenal carboxylate esters whose gamma-hydroxy-alpha,beta-unsaturated aldehyde functionality and reactivity resemble that of HNE.

Topics: Adjuvants, Immunologic; Animals; Antibody Specificity; Arachidonic Acid; Arteriosclerosis; Binding, Competitive; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Epitopes; Hemocyanins; Humans; Kidney Failure, Chronic; Linoleic Acid; Lipoproteins, LDL; Oxidation-Reduction; Pyrroles; Rabbits; Serum Albumin

Alterations in low-density lipoprotein (LDL) composition in diabetes affect its function with respect to control of de novo cholesterol synthesis. We examined the effect of 4 weeks of an oleic-acid-rich diet on LDL composition and function in eight Type 2 diabetic and eight non-diabetic control subjects. LDL (density 1.019-1.063 g/l) was isolated by sequential ultracentrifugation. LDL composition was measured and LDL fatty acids were determined by gas liquid chromatography. Cholesterol synthesis was measured by [14C]-acetate incorporation into the freshly isolated mononuclear leucocytes. Fasting blood glucose fell from 9.3 +/- 2.0 to 8.2 +/- 1.2 mmol/l (p < 0.05) and fasting serum insulin increased from 8.3 +/- 2.8 to 10.4 +/- 5.0 mIU/l (p > 0.05) in the diabetic patients. LDL oleic acid increased in the diabetic patients from 18.8 +/- 1.8% to 22.5 +/- 1.9% (p < 0.01) and in the non-diabetic subjects from 19.9 +/- 1.8% to 23.3 +/- 2.8% (p < 0.01). The LDL-esterified to free cholesterol ratios of 3.0 +/- 0.6 and 2.7 +/- 0.2 for the diabetic and non-diabetic patients were similar, and decreased significantly (p < 0.01) to 2.4 +/- 0.5 and 2.2 +/- 0.4, respectively. Baseline [14C]-acetate incorporation was similar in the two groups, and decreased after diet from 437 +/- 239 to 249 +/- 144 ng/g cell protein (p < 0.05) in the diabetic patients. There was a negative correlation between the LDL-esterified to free cholesterol ratio and the ratio of oleic to linoleic acid in the LDL (r = -0.39, p < 0.05) and a negative correlation between fasting blood glucose and LDL oleic acid in the diabetic patients (r = -0.51, p < 0.05). Enrichment of LDL with oleic acid appears to improve its ability to regulate endogenous cholesterol synthesis in both control and diabetic subjects. In the diabetic population, the diet had a favourable effect on glycaemic control.

Topics: Acetates; Adult; Arachidonic Acid; Arteriosclerosis; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Linoleic Acid; Linoleic Acids; Lipoproteins, LDL; Male; Middle Aged; Oleic Acid; Oleic Acids

Factors implicated in the development of atherosclerosis include metabolic alterations of the endothelium induced by certain lipids and inflammatory cytokines. To study the hypothesis that the combined presence of unsaturated fatty acids and inflammatory cytokines may cross-amplify their individual injurious effects, cultured endothelial cells were treated with 90 mu M of linoleic acid (18:2 n-6) and/or 20 ng/ml (100 U/ml) of tumor necrosis factor-alpha (TNF) for up to 24 h. Disturbances in endothelial cell metabolism were determined by measuring cellular oxidative stress, oxidative stress-inducible nuclear factor-kappa B (NF-kappa B) and NF-kappa B-related transcription, intracellular calcium levels, and endothelial barrier function reflected by transendothelial albumin movement. Both 18:2 and TNF increased cellular oxidation, intracellular calcium, and endothelial barrier permeability. These changes were cross-amplified in cells treated both with 18:2 and TNF, compared with 18:2 or TNF alone. In contrast, a combined exposure to 18:2 and TNF did not potentiate effects mediated by 18:2 or TNF alone on NF-kappa B activation or NF-kappa B-related transcription. Pretreatment with 25 mu M vitamin E attenuated 18:2 and/or TNF-mediated endothelial cell dysfunction. These results suggest that certain unsaturated fatty acids can potentiate TNF-mediated endothelial cell dysfunction and that oxidative stress may be partially responsible for these metabolic events. These findings have implications for understanding lipid-mediated inflammatory responses in atherosclerosis.

Topics: Animals; Arteriosclerosis; Dose-Response Relationship, Drug; Drug Interactions; Endothelium, Vascular; Linoleic Acid; Linoleic Acids; Oxidative Stress; Pulmonary Artery; Swine; Transcription, Genetic; Tumor Necrosis Factor-alpha; Vitamin E

Topics: alpha-Linolenic Acid; Animals; Arteriosclerosis; Coronary Disease; Dietary Fats, Unsaturated; Fatty Acids, Essential; Humans; Infant, Newborn; Linoleic Acid; Linoleic Acids; Lipoproteins, LDL; Thrombosis

Oxidative modification of LDL increases its atherogenicity, and 15-lipoxygenase (15-LO) has been implicated in the process. To address this issue, we generated transgenic rabbits that expressed 15-LO in a macrophage-specific manner and studied their susceptibility to atherosclerosis development when they were fed a high-fat, high-cholesterol (HFHC) diet (Teklad 0533 rabbit diet 7009 with 10% corn oil and 0.25% cholesterol) for 13.5 wk. Transgenic and nontransgenic rabbits developed similar degrees of hypercholesterolemia and had similar levels of triglyceride, VLDL, LDL, and HDL. Quantitative morphometric analysis of the aortic atherosclerosis indicated that the transgenic animals (n = 19) had significantly smaller lesion areas (9.8+/-6.5%, mean+/-SD) than their littermate controls (n = 14, 17.8+/-15.0%) (P < 0.05). In a subgroup (n = 9) of transgenic rabbits that received the HFHC diet plus the antioxidant N',N '-diphenyl-phenylenediamine (1%), the extent of lesion involvement (9.8+/-7.5%) did not differ from the subgroup (n = 10) that received the regular HFHC diet (9.7+/-5.9%). Since the results were unexpected, we repeated the experiments. Again, we found that the nontransgenic littermates (n = 12) had more extensive lesions (11.6+/-10.6%) than the transgenic rabbits (n = 13; 9.5+/-7.8%), although the difference was not significant. In a third set of experiments, we crossed 15-LO transgenic rabbits with Watanabe heritable hyperlipidemic (WHHL) rabbits and found that the lesion area in the 15-LO transgenic/heterozygous WHHL rabbits (n = 14) was only about one third (7.7+/-5.7%) that found in nontransgenic heterozygous WHHL littermate controls (n = 11, 20.7+/-19.4%) (P < 0.05). These data suggest that overexpression of 15-LO in monocytes/macrophages protects against lipid deposition in the vessel wall during early atherogenesis in these rabbit models of atherosclerosis.

Topics: Animals; Animals, Genetically Modified; Aorta; Arachidonate 15-Lipoxygenase; Arteriosclerosis; Cholesterol, Dietary; Chromatography, High Pressure Liquid; Dietary Fats; Gene Expression Regulation; Hypercholesterolemia; Linoleic Acid; Linoleic Acids; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Macrophages; Rabbits; Triglycerides

We tested the hypothesis that an increased content of n-6 polyunsaturated fatty acids (principally linoleic acid) in an atherogenic diet of nonhuman primates would decrease atherosclerosis by modifying the composition and decreasing the concentration of plasma low-density lipoprotein (LDL). A species readily susceptible to diet-induced atherosclerosis (cynomolgus monkey) was compared with a less-susceptible species (African green monkey) with dietary cholesterol concentration and saturated or polyunsaturated fat (40% of energy) as variables. In both species, cholesterol concentrations in whole plasma, LDL, and high-density lipoprotein (HDL) were 20-30% lower when polyunsaturated fat was fed, whereas dietary cholesterol increased LDL cholesterol three- to fourfold. LDL was enriched in cholesteryl oleate when saturated fat and cholesterol were fed. Dietary linoleic acid prevented cholesteryl oleate enrichment and promoted cholesteryl linoleate accumulation in LDL. At the same plasma cholesterol concentration, cynomolgus monkeys had higher LDL cholesterol and lower HDL-cholesterol concentrations than did African green monkeys. LDL particle size was significantly (P < 0.001) larger in the group of cynomolgus monkeys fed polyunsaturated fat but tended to be smaller in African green monkeys fed polyunsaturated fat. Dietary polyunsaturated fat protected against coronary artery atherosclerosis in both species. Thus, LDL particle size, per se, was not atherogenic; instead, coronary artery atherosclerosis and cholesteryl oleate enrichment of LDL were more highly correlated. This outcome suggests that information about LDL composition may be more important for understanding the pathogenesis of atherosclerosis than previously suspected.

Topics: Animals; Arteriosclerosis; Chlorocebus aethiops; Cholesterol, HDL; Dietary Fats, Unsaturated; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Linoleic Acid; Linoleic Acids; Lipoproteins, HDL; Lipoproteins, LDL; Macaca fascicularis; Male

Oxidized low density lipoproteins (LDL) are cytotoxic to cultured endothelial cells and thereby are potentially involved in endothelial cell injury and atherogenesis. Oxidized phospholipids of oxLDL undergo spontaneous hydrolysis (PL-hydrolysis) by LDL-associated phospholipase A2 (PLA2) activities. The present study aimed to investigate whether hydrolysis of oxidized phospholipids contained in mildly oxLDL could influence their cytotoxicity to cultured endothelial cells. PL-hydrolysis (spontaneous or mediated by exogenous PLA2) of mildly oxLDL elicited a significant reduction of their cytotoxicity to cultured endothelial cells. The reduced cytotoxicity of PL-hydrolysed oxLDL was not due to their reduced uptake by cells, but rather to their reduced content of oxidation products which are liberated by PL-hydrolysis and released (at least the more polar compounds) in the aqueous phase, as shown by ultrafiltration experiments. Oxidation products released in the aqueous phase were not or only slightly cytotoxic to endothelial cells, probably because a selective uptake of non oxidized fatty acids as shown by studies of uptake of oxidized and non oxidized [1-14C]linoleic acid. These data suggest that during PL-hydrolysis of mildly oxLDL, (i) oxidized phospholipids are hydrolysed; (ii) oxidation products liberated from oxLDL particles are released (at least in part) to the aqueous phase; (iii) the cytotoxicity of oxLDL to endothelial cells is reduced, probably because oxidized free fatty acids (released by PL-hydrolysis towards the aqueous phase) are not taken up by the cells. Finally, the possibility of a favourable role of PL-hydrolysis of oxLDL against atherogenesis is discussed.

Topics: Animals; Arteriosclerosis; Carbon Radioisotopes; Cattle; Cell Line; Cytotoxins; Endothelium, Vascular; Hydrolysis; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Lipoproteins, LDL; Oxidation-Reduction; Phospholipids

An excess of Oxidative Stress can occur either through an increase in the generation of free radicals and their metabolites (which overwhelm the protective capacity of the normal defence mechanisms of the body) or through a decrease in the protective ability of the body to withstand normal Oxidative Stress or both. Excessive Oxidative Stress plays an important role in the pathogenesis of diabetes and its chronic complications like retinopathy and nephropathy. Through various mechanisms, it plays a prominent role in the progression and acceleration of atherosclerosis. Free radicals being highly unstable due to their high reactivity are very difficult to measure accurately. Recourse is therefore taken to measure the compounds that are formed due to the activity of these free radicals. These compounds are relatively more stable and therefore can be measured as diene congugate and lipid peroxides. Another valuable measurement is to measure the levels of reduced glutathione in serum. Measurements of these products can be an excellent parameter to judge the metabolic control of diabetes.

Topics: Adult; Aged; Antioxidants; Arteriosclerosis; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Evaluation Studies as Topic; Female; Free Radicals; Glutathione; Humans; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Male; Middle Aged; Myocardial Ischemia; Oxidative Stress

Conjugated linoleic acid (CLA) consists of a series of positional and geometric dienoic isomers of linoleic acid that occur naturally in foods. CLA exhibits antioxidant activity in vitro and in vivo. To assess the effect of CLA on atherosclerosis, 12 rabbits were fed a semi-synthetic diet containing 14% fat and 0.1% cholesterol for 22 weeks. For 6 of these rabbits, the diet was augmented with CLA (0.5 g CLA/rabbit per day). Blood samples were taken monthly for lipid analysis. By 12 weeks total and LDL cholesterol and triglycerides were markedly lower in the CLA-fed group. Interestingly, the LDL cholesterol to HDL cholesterol ratio and total cholesterol to HDL cholesterol ratio were significantly reduced in CLA-fed rabbits. Examination of the aortas of CLA-fed rabbits showed less atherosclerosis.

Topics: Animals; Aorta; Arteriosclerosis; Cholesterol; Female; Linoleic Acid; Linoleic Acids; Lipids; Liver; Male; Rabbits

Quick model of experimental atherosclerosis--3 weeks of cholesterol feeding and 3 weeks of standard diet for aorta atheromatosis development--was used in rabbits. Then one group of animals was fed 1 month by plant oil of specific composition, with added omega-3 (linolenic) fatty acid, and the other group received the same dose of fish oil. The most intensive decrease of plasma cholesterol and erythrocyte cholesterol/phospholipid ratio was in rabbits, that received the oil with linolenic acid. Triglyceride level decreased gradually in all animal groups in the same degree, and HOL cholesterol did not change. After the end of experiment the aorta damage degree in group, that received plant oil with linolenic acid, was only 10.8%, as compared with 36.2% in control group (without treatment) and 39.3% in rabbits, that received fish oil. The absence of fish oil effect supports the earlier data about rabbits specific sensitivity to this product resulting in possible hepatotoxic effect. The data indicates on the usefulness of rabbit model in fish oil effects investigations, and also on the positive, antiatherogenic effect of plant oil with added linolenic acid.

Topics: Animals; Arteriosclerosis; Diet, Atherogenic; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fatty Acids, Omega-3; Fish Oils; Linoleic Acid; Linoleic Acids; Male; Plant Oils; Rabbits; Time Factors

We tried to develop an experimental model using mice for the primary screening of antiatherosclerotic agents. Male ICR strain mice were given a high-cholesterol diet supplemented with 10% linoleic acid for 14 weeks. Throughout the experimental period, weight gain of these mice was significantly inhibited as compared to that of control mice given a basal diet, but displayed a steady increase comparable to that of the high-cholesterol diet without linoleic acid. The cholesterol and linoleic acid-fed mice showed increased serum cholesterol and phospholipid levels, and decreased serum triglyceride and high-density lipoprotein-(HDL) cholesterol levels and lecithin/cholesterol acyltransferase (LCAT) activity, as well as a markedly increased lipid peroxide level which was a characteristic appearance in the serum of this mouse model. At the end of the experiment, uniform and significant increases in cholesterol, notably cholesteryl ester, were observed in the aorta. Also found were marked decreases in the aorta contents of desmosine and isodesmosine, which are cross-linking amino acids present only in the elastin. Histological observations showed accumulations of fatty droplets in the intima. These changes were much less in mice receiving a high-cholesterol diet without linoleic acid. In this mouse model, probucol prevented elevation of serum cholesterol, phospholipid, and cholesterol accumulation in the aorta. Increases in lipid peroxide level and decreases in LCAT activity were also prevented. These findings indicate that this mouse model is useful for primary screening of antiatherosclerotic agents with antioxidative activity.

Topics: Animals; Anticholesteremic Agents; Aorta; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Desmosine; Disease Models, Animal; Drug Evaluation, Preclinical; Hypercholesterolemia; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Lipids; Male; Mice; Mice, Inbred ICR; Phosphatidylcholine-Sterol O-Acyltransferase; Probucol

Non-enzymatic glycation of reactive amino groups in model proteins increased the rate of free radical production at physiologic pH by nearly fifty-fold over non-glycated protein. Superoxide generation was confirmed by electron paramagnetic resonance measurements with the spin-trap phenyl-t-butyl-nitrone. Both Schiff base and Amadori glycation products were found to generate free radicals in a ratio of 1:1.5. Free radicals generated by glycated protein increased peroxidation of membranes of linoleic/arachidonic acid vesicles nearly 2-fold over control, suggesting that the increased glycation of proteins in diabetes may accelerate vascular wall lipid oxidative modification.

Topics: Arteriosclerosis; Catalase; Cell Membrane; Cyclic N-Oxides; Cytochrome c Group; Diabetes Complications; Diabetes Mellitus; Electron Spin Resonance Spectroscopy; Free Radicals; Glucose; Humans; Hyperglycemia; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Nitroblue Tetrazolium; Nitrogen Oxides; Schiff Bases; Spin Labels; Superoxide Dismutase

An atherogenic diet (AD) consisting entirely of normal foods for westernized people was fed to female Vervet monkeys for 4 years. The plasma low density lipoprotein (LDL) cholesterol pool was increased and progression of atherosclerosis was enhanced by the AD compared to a more prudent Western diet. The increased LDL-cholesterol was carried by a 3-fold increase in particles of relatively normal composition and not by packing cholesterol esters into the cores of enlarged LDL particles, as has been reported after feeding semisynthetic diets loaded with extra cholesterol. Nevertheless, these LDL particles were atherogenic. The AD changed the fatty acid composition of LDL-cholesterol esters and triacylglycerol, notably by increasing arachidonic and reducing linoleic acid. Multivariate analysis showed that measures and scores of atherosclerosis were significantly dependent on sphingomyelin and phosphatidylcholine in LDL and on arachidonic acid in LDL-triacylglycerol. Although apolipoprotein B, free cholesterol, esterified cholesterol and lysophosphatidylcholine in plasma LDL and atherosclerosis were significantly positively correlated in bivariate analysis they were not selected by multivariate analysis as the strongest determinants of atherogenesis. Cholesterol in plasma high density lipoprotein was not changed by the AD and lecithin:cholesterol acyltransferase activity in plasma was inversely linked to atherosclerosis. Subcutaneous fatty acids reflected dietary fatty acids.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Chlorocebus aethiops; Cholesterol, LDL; Diet, Atherogenic; Female; Linoleic Acid; Linoleic Acids; Particle Size

Human low density lipoproteins radiolabeled with 125I transfer across confluent monolayers of cultured porcine pulmonary artery endothelial cells. The amount transferred was dependent on the low density lipoprotein concentration and was not saturable at concentrations up to 300 micrograms protein per 0.5 ml medium. Gel filtration showed that more than 90% of the 125I which crossed the endothelial monolayer remained associated with low density lipoproteins, indicating that appreciable amounts of lipoprotein were not degraded during the transfer process. When the endothelial monolayer was exposed for 24 hours to culture media supplemented with 100-300 microM fatty acid complexed with 100 microM albumin, the amount of low density lipoprotein subsequently transferred increased by 65% to 150%. The extent of the increase was dependent on the type of fatty acid added and its concentration. At 200 microM, albumin-bound oleic and linoleic acids increased low density lipoprotein transfer, whereas palmitic, linolenic, arachidonic, and eicosapentaenoic acids did not. These results are consistent with the hypothesis that exposure of the endothelium to elevated concentrations of fatty acid may allow excessive amounts of cholesterol-rich lipoproteins to enter the arterial intima.

Topics: Animals; Arteries; Arteriosclerosis; Cells, Cultured; Endothelium; Fatty Acids; Humans; Linoleic Acid; Linoleic Acids; Lipoproteins, LDL; Oleic Acid; Oleic Acids; Pulmonary Artery; Swine

While the content of fatty streaks and fibrous plaques has been extensively studied in autopsied specimens, little is known about the lipid composition of advanced human atherosclerotic plaques requiring surgical removal. We have analyzed free cholesterol, cholesteryl ester, and the cholesteryl ester fatty acid content in 19 carotid and 7 femoral obliterative plaques obtained at endarterectomy. These were compared with values from each subject's plasma and from xanthomas removed from eight patients. The total cholesterol content was 75.1 mg/g dry weight for carotid plaques, 56.0 mg/g for femoral plaques, and 106.8 mg/g for xanthomas. The free cholesterol content was 56.6% and 50.4% of the total cholesterol for carotid and femoral plaques, respectively, while the free cholesterol of xanthomas was only 25.5%. The fatty acids of cholesteryl esters were analyzed in an attempt to identify the site of their esterification, i.e., within plasma or within plaque. This can be determined using the ratio of linoleic acid (18:2) to oleic acid (18:1) in the cholesteryl ester. The ratios were 0.36 for xanthoma, 1.62 for carotid plaque, 1.73 for femoral plaque, and 2.51 in plasma. These data emphasize two chemical changes occurring with evolution of the atherosclerotic process: 1) The cholesteryl ester fatty acid composition of the plaque becomes increasingly similar to that of plasma, and 2) there is a continuing increase in the percentage of free cholesterol. These alterations reflect a decreased metabolic efficiency within atherosclerotic lesions and may initiate events that enhance plaque progression.

Topics: Arteriosclerosis; Autopsy; Cholesterol Esters; Humans; Linoleic Acid; Linoleic Acids; Lipids; Oleic Acid; Oleic Acids

Topics: Adipose Tissue; Arteriosclerosis; Biomedical Research; Blood; Cholesterol; Coronary Disease; Diet; Dietary Fats; Fatty Acids; Geriatrics; Glycerides; Humans; Linoleic Acid; Lipids; Phospholipids; Preventive Medicine; United States; Vitamin E

Topics: Animals; Arteriosclerosis; Atherosclerosis; Cholesterol; Diet; Diet, Atherogenic; Linoleic Acid; Linoleic Acids; Lipid Metabolism; Pathology; Pharmacology; Rabbits; Research

Topics: Arteriosclerosis; Cholagogues and Choleretics; Dextrans; Fatty Acids; Heparinoids; Linoleic Acid; Lipid Metabolism; Niacin; Nicotinic Acids; Phenylbutyrates; Pyridoxal Phosphate; Sterols; Thyroid Hormones; Triparanol

Topics: Arteriosclerosis; Blood Chemical Analysis; Cholesterol; Diet; Dietary Fats; Dietary Fats, Unsaturated; Fats, Unsaturated; Linoleic Acid; Pharmacology

Topics: Animals; Aorta; Arteriosclerosis; Body Weight; Butter; Cholesterol; Coronary Vessels; Diet; Dietary Fats; Hypercholesterolemia; Kidney; Linoleic Acid; Liver; Metabolism; Myocardium; Oils; Oils, Volatile; Pathology; Rabbits; Research; Starch

Topics: Arteriosclerosis; Chemical Phenomena; Chemistry; Deficiency Diseases; Diabetes Mellitus; Dietary Fats; Fats; Fatty Acids; Fatty Acids, Essential; Humans; Hypothyroidism; Linoleic Acid; Lipids; Oils; Oleic Acid; Oleic Acids

Topics: Anticoagulants; Arteriosclerosis; Biomedical Research; Fatty Acids; Fatty Acids, Essential; Linoleic Acid; Preventive Medicine; Thrombosis

Topics: Animals; Aorta; Arteriosclerosis; Cholesterol; Chromatography; Dietary Fats; Glycerides; Hydrocarbons; Lecithins; Linoleic Acid; Lipids; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Rabbits; Research; Stereoisomerism

Topics: Arteriosclerosis; Chromatography; Diabetes Mellitus; Diabetic Angiopathies; Fatty Acids; Fatty Acids, Essential; Glycerides; Healthy Volunteers; Linoleic Acid; Lipids; Phospholipids

Topics: Arteriosclerosis; Dietary Fats; Erythrocytes; Fatty Acids; Linoleic Acid; Lipids; Myocardial Infarction; Phospholipids; Statistics as Topic

Topics: Animals; Arteriosclerosis; Blood Chemical Analysis; Cholesterol; Diet; Dietary Fats; Fatty Acids; Linoleic Acid; Lipids; Palmitic Acid; Phospholipids; Rabbits; Research; Stearic Acids

Topics: Animals; Arteriosclerosis; Cholesterol; Dietary Fats; Fats; Glycine max; Linoleic Acid; Linoleic Acids; Liver; Rats; Thiouracil

Topics: Aorta; Arteriosclerosis; Atherosclerosis; Carbon Isotopes; Cholesterol; Cholesterol Esters; Linoleic Acid; Lipid Metabolism; Liver; Oleic Acid; Rabbits; Research

Topics: Animals; Arteriosclerosis; Atherosclerosis; Blood Chemical Analysis; Body Weight; Cholesterol; Dietary Proteins; Fatty Acids; Fatty Acids, Essential; Heparin; Hexosamines; Hypertension; Hypertension, Renal; Lanolin; Linoleic Acid; Lipoproteins; Pathology; Phospholipids; Rabbits; Research; Urea

Topics: Aortic Valve Stenosis; Arteriosclerosis; Bronchitis; Cholelithiasis; Diabetes Mellitus; Fatty Acids; Geriatrics; Hypertension; Injections, Intravenous; Kidney Function Tests; Linoleic Acid; Lung Diseases; Myocardial Infarction; Neurocirculatory Asthenia; Oleic Acid; Pharmacology; Phosphatidylcholines; Phospholipids; Pleurisy

Topics: Arteriosclerosis; Atherosclerosis; Dietary Fats; Glycerides; Heparin; Heparinoids; Hypercholesterolemia; Hyperlipidemias; Linoleic Acid; Lipid Metabolism; Lipoprotein Lipase; Niacin

Topics: Arachidonic Acid; Arteriosclerosis; Cholesterol; Hypercholesterolemia; Linoleic Acid; Nutrition Therapy; Pyridoxine; Vitamin B 6

Topics: Arteriosclerosis; Atherosclerosis; Blood Proteins; Cholesterol; Diet; Fatty Acids; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Lipids; Nutrition Assessment

Topics: alpha-Linolenic Acid; Arachidonic Acid; Arteriosclerosis; Atherosclerosis; Humans; Linoleic Acid; Lipoproteins

Topics: Acetates; Animals; Arteriosclerosis; Atherosclerosis; Chickens; Cholesterol; Linoleic Acid; Pyridoxine; Vitamin B 6

Topics: Animals; Arteriosclerosis; Cholesterol; Fatty Acids, Unsaturated; Linoleic Acid; Rabbits