vitamin-k-semiquinone-radical and Arteriosclerosis

Peripheral arterial disease (PAD) is frequently treated by either an infrainguinal autologous (using the patient's own veins) or synthetic graft bypass. The rate of occlusion of the graft after one year is between 12% and 60%. To prevent occlusion, patients are treated with an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion. This is an update of a Cochrane review first published in 2003.. To evaluate whether antithrombotic treatment improves graft patency, limb salvage and survival in patients with chronic PAD undergoing infrainguinal bypass surgery.. The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3).. Randomised, controlled trials; two review authors independently assessed the methodological quality of each trial using a standardised checklist.. Data collected included patient details, inclusion and exclusion criteria, type of graft, antithrombotic therapy, outcomes, and side effects.. A total of 14 trials were included in this review; 4970 patient results were analysed. Four trials evaluating vitamin K antagonists (VKA) versus no VKA suggested that oral anticoagulation may favour autologous venous, but not artificial, graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin (ASA) or aspirin and dipyridamole provided evidence to support a positive effect of VKA on the patency of venous but not artificial grafts. Three trials comparing low molecular weight heparin (LMWH) to unfractionated heparin (UFH) failed to demonstrate a significant difference on patency. One trial comparing LMWH with placebo found no significant improvement in graft patency over the first postoperative year in a population receiving aspirin. One trial showed an advantage for LMWH versus aspirin and dipyridamol at one year for patients undergoing limb salvage procedures. Perioperative administration of ancrod showed no greater benefit when compared to unfractionated heparin. Dextran 70 showed similar graft patency rates to LMWH but a significantly higher proportion of patients developed heart failure with dextran.. Patients undergoing infrainguinal venous graft are more likely to benefit from treatment with VKA than platelet inhibitors. Patients receiving an artificial graft benefit from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers are needed in the future to compare antithrombotic therapies with either placebo or antiplatelet therapies.

Topics: Arteriosclerosis; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Intermittent Claudication; Ischemia; Leg; Peripheral Vascular Diseases; Randomized Controlled Trials as Topic; Thrombosis; Vitamin K

Arteriosclerosis, characterized by remodeling and stiffening of large elastic arteries is the most significant manifestation of vascular aging. The increased stiffening is believed to originate from a gradual mechanical senescence of the elastic network, alterations in cross-linking of extracellular matrix components, fibrosis and calcification of elastic fibers (medial elastocalcinosis). The stiffening of large arteries reduces their capacitance and accelerates pulse wave velocity, thus contributing to a widening of pulse pressure and to the increased prevalence of isolated systolic hypertension with age. Current antihypertensive drugs were mainly designed to reduce peripheral resistance and are not adequate to alter the pathological process of vascular stiffening or even to selectively reduce systolic blood pressure in isolated systolic hypertension. This review puts forward the concept that elastocalcinosis is a valuable therapeutic target and presents evidence that this process can be prevented and reversed pharmacologically.

Topics: Aged; Aging; Antihypertensive Agents; Arteries; Arteriosclerosis; Calcinosis; Humans; Hypertension; Muscle, Smooth, Vascular; Osteoporosis; Systole; Vitamin K; Warfarin

The role of vitamin K in the prevention and treatment of osteoporosis and arterial calcification is examined.. Vitamin K is essential for the activation of vitamin K-dependent proteins, which are involved not only in blood coagulation but in bone metabolism and the inhibition of arterial calcification. In humans, vitamin K is primarily a cofactor in the enzymatic reaction that converts glutamate residues into gamma-carboxyglutamate residues in vitamin K-dependent proteins. Numerous studies have demonstrated the importance of vitamin K in bone health. The results of recent studies have suggested that concurrent use of menaquinone and vitamin D may substantially reduce bone loss. Menaquinone was also found to have a synergistic effect when administered with hormone therapy. Several epidemiologic and intervention studies have found that vitamin K deficiency causes reductions in bone mineral density and increases the risk of fractures. Arterial calcification is an active, cell-controlled process that shares many similarities with bone metabolism. Concurrent arterial calcification and osteoporosis have been called the "calcification paradox" and occur frequently in postmenopausal women. The results of two dose-response studies have indicated that the amount of vitamin K needed for optimal gamma-carboxylation of osteocalcin is significantly higher than what is provided through diet alone and that current dosage recommendations should be increased to optimize bone mineralization. Few adverse effects have been reported from oral vitamin K.. Phytonadione and menaquinone may be effective for the prevention and treatment of osteoporosis and arterial calcification.

Topics: Antifibrinolytic Agents; Arteriosclerosis; Female; Humans; Osteoporosis, Postmenopausal; Treatment Outcome; Vitamin K; Vitamin K 1; Vitamin K 2

Vitamin K is well known for its role in the synthesis of a number of blood coagulation factors. During recent years vitamin K-dependent proteins were discovered to be of vital importance for bone and vascular health. Recommendations for dietary vitamin K intake have been made on the basis of the hepatic requirements for the synthesis of blood coagulation factors. Accumulating evidence suggests that the requirements for other functions than blood coagulation may be higher. This paper is the result of a closed workshop (Paris, November 2002) in which a number of European vitamin K experts reviewed the available data and formulated their standpoint with respect to recommended dietary vitamin K intake and the use of vitamin K-containing supplements.

Topics: Antifibrinolytic Agents; Arteriosclerosis; Bone and Bones; Calcinosis; Dietary Supplements; Fractures, Bone; Humans; Nutritional Requirements; Osteocalcin; Osteoporosis; Safety; Vitamin K; Vitamin K Deficiency

Recent advances in the discovery of new functions for vitamin K-dependent (VKD) proteins and in defining vitamin K nutriture have led to a substantial revision in our understanding of vitamin K physiology. The only unequivocal function for vitamin K is as a cofactor for the carboxylation of VKD proteins which renders them active. While vitamin K was originally associated only with hepatic VKD proteins that participate in hemostasis, VKD proteins are now known to be present in virtually every tissue and to be important to bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction. The development of improved methods for analyzing vitamin K has shed considerable insight into the relative importance of different vitamin K forms in the diet and their contribution to hepatic vs. non-hepatic tissue. New assays that measure the extent of carboxylation in VKD proteins have revealed that while the current recommended daily allowance for vitamin K is sufficient for maintaining functional hemostasis, the undercarboxylation of at least one non-hemostatic protein is frequently observed in the general population. The advances in defining VKD protein function and vitamin K nutriture are described, as is the potential impact of VKD proteins on atherosclerosis. Many of the VKD proteins contribute to atherogenesis. Recent studies suggest involvement in arterial calcification, which may be influenced by dietary levels of vitamin K and by anticoagulant drugs such as warfarin that antagonize vitamin K action.

Topics: Animals; Anticoagulants; Arteriosclerosis; Chemotaxis; Hemostasis; Humans; Liver; Models, Biological; Models, Chemical; Nutritional Physiological Phenomena; Protein Structure, Tertiary; Risk Factors; Signal Transduction; Vitamin K

Chronic peripheral arterial disease (PAD) is frequently treated by implantation of either an infrainguinal autologous venous or artificial graft. One-year occlusion rates for infrainguinal bypasses vary between 15 and 75%, depending on the site of distal anastomosis, length, quality, and material of the graft, but also on other factors such as proximal inflow and distal outflow conditions. To prevent graft occlusion, patients are usually treated with either an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion.. To evaluate whether antithrombotic treatment in patients with chronic PAD undergoing infrainguinal bypass surgery improves graft patency, limb salvage and survival by performing a meta-analysis of performed RCTs.. The search strategy was that adopted by the Cochrane Review Group on Peripheral Vascular Diseases. Additional data bases were reviewed (Reference lists of papers resulting from this search, MEDLINE from 1966-onwards and EMBASE from 1980-onwards using the terms 'anticoagulant' and 'arterial surgery'.. The methodological quality of each trial was assessed independently by at least two reviewers using the checklist provided by the Peripheral Vascular Diseases Collaborative Review Group, with emphasis on concealment of randomisation. Each trial was given an allocation score of A (clearly concealed), B (unclear if concealed), or C (clearly not concealed) and a summary score of A (low risk of bias), B (moderate risk), or C (high risk). Trials scoring A were included and those scoring C were excluded. For a trial scoring B, an attempt was made to obtain more information by contacting the author.. For each trial, the number of patients originally allocated to each treatment group was extracted from the data and an 'intention to treat' analysis performed. Data collection on each trial included inclusion and exclusion criteria, patient details, type of graft, type and dose of antithrombotic therapy used, outcome, and side effects. The treatment and control groups were compared for important prognostic factors and differences described. If any of the above data was not available, further information was sought from the author. However, the heterogeneity between trials could not be tested due to inaccessible data. Data were synthesized by comparing group results.. The analysis including four trials which evaluated vitamin K antagonists (VKA) versus no VKA indicate, that oral anticoagulation tendentially favours venous but not artificial graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin or aspirin/dipyridamole supported evidence for a positive effect of VKA on the patency of venous but not artificial grafts. Subgroup analysis for artificial grafts as performed in one trial showed a favourable effect of antiplatelet agents on synthetic bypasses. In two trials with a relatively small number of patients low molecular weight heparin treatment was associated with a lower incidence of early postoperative graft thrombosis compared to treatment with unfractionated heparin. In one trial infusion of antithrombin concentrate was reported to have a negative effect on intraoperative graft thrombosis necessitating the study to be stopped before termination. Perioperative administration of ancrod was compared to unfractionated heparin showing no benefit of one drug compared to the other.. Patients operated for an infrainguinal venous graft might benefit from treatment with VKA, whereas patients receiving an artificial graft might profit more from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers comparing antithrombotic therapies with either placebo or antiplatelet therapies are called for in the future.

Topics: Arteriosclerosis; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Intermittent Claudication; Ischemia; Leg; Peripheral Vascular Diseases; Postoperative Complications; Randomized Controlled Trials as Topic; Thrombosis; Vitamin K

Over the last 30 years, a growing body of evidence has documented the role of hyperhomocysteinemia (HHcy) as an independent vascular risk factor. However, the mechanisms through which elevated circulating levels of homocysteine (Hcy) cause vascular injury and promote thrombosis remain elusive. Most findings have been achieved in in vitro studies employing exceedingly high concentrations of Hcy, whereas only a few studies have been carried out in vivo in humans. In homocystinuric patients, homozygotes for mutations of the gene coding for the cystathionine beta-synthase enzyme, abnormalities of coagulation variables reflecting a hypercoagulable state, have been reported. In vitro studies provide a biochemical background for such a state. In homocystinuric patients, an in vivo platelet activation has also been reported. The latter abnormality is not corrected by the bolus infusion of concentrations of hirudin, which determines a long-lasting impairment of the conversion of fibrinogen to fibrin by thrombin; in contrast, it appears at least in part lowered by the administration of the antioxidant drug probucol. During the autooxidation of Hcy in plasma, reactive oxygen species are generated. The latter initiate lipid peroxidation in cell membranes (potentially responsible for endothelial dysfunction) and in circulating lipoproteins. Oxidized low-density lipoproteins (LDL) may trigger platelet activation as well as some of the hemostatic abnormalities reported in such patients. Thus the oxidative stress induced by Hcy may be a key process in the pathogenesis of thrombosis in HHcy. Accumulation of adenosylhomocysteine in cells (a consequence of high circulating levels of homocysteine) inhibits methyltransferase enzymes, in turn preventing repair of aged or damaged cells. This mechanism has been recently documented in patients with renal failure and HHcy and provides an additional direction to be followed to understand the tendency to thrombosis in moderate HHcy.

Topics: Adolescent; Adult; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Cellular Senescence; Child; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Lipid Peroxidation; Lipoproteins, LDL; Male; Methyltransferases; Oxidation-Reduction; Platelet Activation; Reactive Oxygen Species; Renal Insufficiency; Risk Factors; S-Adenosylhomocysteine; Thrombophilia; Thromboxane B2; Vitamin K

It is well-known that vitamin K has a strong blood coagulation activity by acting a cofactor for gamma-carboxylase which catalizes the conversion of specific glutamic acid residue to gamma-carboxyglutamic acid residue (Gla). Some of the Gla-containing proteins, such as osteocalcin and matrix Gla protein have been found in calcifying tissues. These proteins are considered to play an important role in Ca-deposition. Recent studies have clearly demonstrated the substantial role of vitamin K in bone metabolism that has been developed for clinical use. Furthermore, diverse physiological activities have been found subsequently as follows: regulation of glucose metabolism, anti-arteriosclerosis, and induction of cell differentiation. Here I introduce the mainly physiological activities of vitamin K2, making a comparison with vitamin K1.

Topics: Arteriosclerosis; Blood Coagulation; Cell Division; Humans; Osteogenesis; Vitamin K

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

Gamma-carboxyglutamic acid is an amino acid with a dicarboxylic acid side chain. This amino acid, with unique metal binding properties, confers metal binding character to the proteins into which it is incorporated. This amino acid has been discovered in blood coagulation proteins (prothrombin, Factor X, Factor IX, and Factor VII), plasma proteins of unknown function (Protein C, Protein S, and Protein Z), and proteins from calcified tissue (osteocalcin and bone-Gla protein). It has also been observed in renal calculi, atherosclerotic plaque, and the egg chorioallantoic membrane, among other tissues. Gamma-carboxyglutamic acid is synthesized by the post-translational modification of glutamic acid residues. This reaction, catalyzed by a hepatic carboxylase, requires reduced vitamin K, oxygen, and carbon dioxide. The function of gamma-carboxyglutamic acid is uncertain. In prothrombin gamma-carboxyglutamic acid residues bound to metal ions participate as an intramolecular non-covalent bridge to maintain protein conformation. Additionally, these amino acids participate in the calcium-dependent molecular assembly of proteins on membrane surfaces through intermolecular bridges involving gamma-carboxyglutamic acid and metal ions.

Topics: 1-Carboxyglutamic Acid; Animals; Arteriosclerosis; Binding Sites; Blood Proteins; Calcification, Physiologic; Calcinosis; Calcium; Calcium-Binding Proteins; Chemical Phenomena; Chemistry; Factor IX; Factor VII; Factor X; Glutamates; Glycoproteins; Humans; Metals; Osteocalcin; Protein C; Protein S; Proteins; Prothrombin; Urinary Calculi; Vitamin K

Topics: Angina Pectoris; Arteriosclerosis; Blood Coagulation; Cerebral Hemorrhage; Chemical Phenomena; Chemistry; Coumarins; Drug Antagonism; Drug Synergism; Female; Hemorrhage; Humans; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Myocardial Infarction; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Embolism; Thrombophlebitis; Vitamin K

Gammacarboxyglutamate (Gla) is an uncommon amino acid formed by vitamin K action. Increasing evidence indicates that Gla-proteins are involved in the regulation of calcification processes in both bone tissue and atherosclerotic vessel wall. In a population-based study we have previously shown that in a group of 113 postmenopausal women the presence of abdominal aortic calcifications is associated with a reduced vitamin K status. In the present study we investigated whether this reduced vitamin K status was also associated with differences in bone mass or circulating calciotropic hormone levels. Serum immunoreactive osteocalcin with low affinity for hydroxyapatite (irOCfree) was used as a marker for vitamin K status. After correction for age it was found that women with atherosclerotic calcifications had a 7% lower bone mass as measured by metacarpal radiogrammetry (mean difference: 3.2 mm2, 95% CI: -0. 2-6.5, P = 0.06). No differences between both groups of women were observed for serum intact parathyroid hormone (PTH) and serum 25-hydroxyvitamin D levels. In the atherosclerotic women (n = 34), markers for vitamin K status were inversely associated with bone mass (r = -0.47, P = 0.013), whereas no such association was found in the nonatherosclerotic women (n = 79). It is concluded that the atherosclerotic women in this study may be at higher risk for osteoporotic fractures as evidenced by their lower bone mass and higher serum irOCfree levels. The finding that in atherosclerotic women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects the mineralization processes in both bone and in atherosclerotic plaques.

Topics: Aged; Aorta; Arteriosclerosis; Bone Density; Cohort Studies; Female; Humans; Middle Aged; Osteocalcin; Osteoporosis; Postmenopause; Risk Factors; Vitamin K

越来越多的研究证实，维生素通过多种途径参与并影响动脉粥样硬化的形成，如改善内皮功能（维生素A、C、D、E）、改善代谢（维生素A、B12、C、D、K）、肾素-血管紧张素-醛固酮系统抑制剂（维生素D）、抗炎（维生素A、D、E、K）、抗氧化（维生素A、C、E）、降低同型半胱氨酸水平（维生素B12）及逆转动脉钙化（维生素K）等。维生素A、B12、C、D、E及K水平对评估心血管风险具重要意义。本文就与动脉粥样硬化相关的几种维生素及其相关机制和临床研究作一综述。.

Topics: Arteriosclerosis; Humans; Vitamin A; Vitamin K; Vitamins

Vitamin K plays a crucial role in the regulation of vascular calcifications by allowing activation of matrix Gla protein. The dietary requirement for vitamin K is low because of an efficient recycling of vitamin K by vitamin K epoxide reductase (VKORC1). However, decreased VKORC1 activity may result in vascular calcification. More than 30 coding mutations of VKORC1 have been described. While these mutations have been suspected of causing anticoagulant resistance, their association with an increase in the risk of vascular calcification has never been considered. We thus investigated functional cardiovascular characteristics in a rat model mutated in VKORC1. This study revealed that limited intake in vitamin K in mutated rat induced massive calcified areas in the media of arteries of lung, aortic arch, kidneys and testis. Development of calcifications could be inhibited by vitamin K supplementation. In calcified areas, inactive Matrix Gla protein expression increased, while corresponding mRNA expression was not modified. Mutation in VKORC1 associated with a limited vitamin K intake is thus a major risk for cardiovascular disease. Our model is the first non-invasive rat model that shows spontaneous medial calcifications and would be useful for studying physiological function of vitamin K.

Topics: Animals; Anticoagulants; Aorta, Thoracic; Arteries; Arteriosclerosis; Disease Models, Animal; Humans; Kidney; Lung; Male; Monckeberg Medial Calcific Sclerosis; Mutation; Mutation, Missense; Polymorphism, Single Nucleotide; Rats; Testis; Vascular Calcification; Vitamin K; Vitamin K Epoxide Reductases

Age-related medial calcification (elastocalcinosis) of large arteries is accelerated in diabetes and appears mainly in distal arteries. The aim was to devise a rat model of elastocalcinosis in association with diabetes to examine the hypothesis that diabetes accelerates vascular calcification experimentally.. Male Wistar rats received a high fat diet during 2 months followed by a low dose of streptozotocin to induce diabetes (D). Elastocalcinosis was facilitated by 3 weeks of treatment with warfarin and vitamin K (WVK). We started WVK treatment 1 week (D4WVK) and 4 weeks (D7WVK) after the injection of streptozotocin and in age-matched healthy rats. Measurements of hemodynamic and metabolic parameters, aortic and femoral calcium content, and immunohistochemistry for alkaline phosphatase, osteopontin, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-TGF-beta were performed.. Three weeks of WVK treatment alone did not increase the calcium content in the aorta and femoral arteries. However, in the D7WVK group, femoral calcification, but not aortic calcium content, increased significantly as compared to the WVK group. This response was not observed in the D4WVK group. In femoral arteries, strong immunostaining for alkaline phosphatase and osteopontin was observed in the D7WVK group. TNF-alpha and TGF-beta expressions were mainly localized in the adventitia of arteries from diabetic rats.. We have established a model of accelerated elastocalcinosis in diabetes related to its duration and localized in distal arteries. The modification of local protein expression is also in accordance with clinical data, suggesting that this model could be useful to investigate mechanisms related to this important clinical macrovascular complication of diabetes.

Topics: Alkaline Phosphatase; Animals; Aorta; Arteriosclerosis; Calcinosis; Calcium; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Femoral Artery; Immunohistochemistry; Male; Models, Animal; Osteopontin; Rats; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vitamin K; Warfarin

To provide a rational basis for recommended daily allowances (RDA) of dietary phylloquinone (vitamin K1) and menaquinone (vitamin K2) intake that adequately supply extrahepatic (notably vascular) tissue requirements.. Vitamin K has a key function in the synthesis of at least two proteins involved in calcium and bone metabolism, namely osteocalcin and matrix Gla-protein (MGP). MGP was shown to be a strong inhibitor of vascular calcification. Present RDA values for vitamin K are based on the hepatic phylloquinone requirement for coagulation factor synthesis. Accumulating data suggest that extrahepatic tissues such as bone and vessel wall require higher dietary intakes and have a preference for menaquinone rather than for phylloquinone.. Tissue-specific vitamin K consumption under controlled intake was determined in warfarin-treated rats using the vitamin K-quinone/epoxide ratio as a measure for vitamin K consumption. Immunohistochemical analysis of human vascular material was performed using a monoclonal antibody against MGP. The same antibody was used for quantification of MGP levels in serum.. At least some extrahepatic tissues including the arterial vessel wall have a high preference for accumulating and using menaquinone rather than phylloquinone. Both intima and media sclerosis are associated with high tissue concentrations of MGP, with the most prominent accumulation at the interface between vascular tissue and calcified material. This was consistent with increased concentrations of circulating MGP in subjects with atherosclerosis and diabetes mellitus.. This is the first report demonstrating the association between MGP and vascular calcification. The hypothesis is put forward that undercarboxylation of MGP is a risk factor for vascular calcification and that the present RDA values are too low to ensure full carboxylation of MGP.

Topics: Arteriosclerosis; Calcinosis; Calcium; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Muscle, Smooth, Vascular; Osteocalcin; Vitamin K; Vitamin K 1

In order to further investigate the radical scavenging and anti-arteriosclerotic activities of vitamin K2 and estradiol, the comparative effects of vitamin K2 and estradiol on aortic calcium (Ca) and inorganic phosphorus (P) levels in the aorta and the elastin fraction (fr.) were investigated in male rats after experimental arteriosclerosis with diabetes mellitus was induced by vitamin D2 and radical producing substance, streptozotocin (STZ). Pharmacological dose of vitamin K2 (100 mg/kg b.w.) and medical dose of estradiol (83 micrograms/kg b.w.) suppressed the increased serum glucose, and vitamin K2 and estradiol increased the decrease in serum insulin. Moreover, vitamin K2 and estradiol inhibited the increase of Ca and P in the aorta and the elastin fr. Vitamin K2 and estradiol decreased the increase in serum lipid peroxide (LPO). It is suggested that both the pharmacological dose of vitamin K2 and medical dose of estradiol suppressed the development of arteriosclerosis associated with diabetes mellitus, owing to radical scavenging activity of vitamin K2 and estradiol.

Topics: Animals; Aorta; Arteriosclerosis; Calcium; Diabetes Mellitus, Experimental; Estradiol; Free Radical Scavengers; Male; Phosphorus; Random Allocation; Rats; Vitamin K

The comparative effects of vitamin K2 and vitamin E on aortic calcium (Ca) and inorganic phosphorus (P) levels in the aorta and the elastin fraction (fr.) were investigated in male rats after experimental arteriosclerosis was induced by vitamin D2 with atherogenic diet. Both vitamin K2 (100 mg/kg b.w.) and vitamin E (40 mg/kg b.w.) inhibited the increase of Ca and P in the aorta and the elastin fr. from the arteriosclerotic rats. Vitamin K2 (50 mg/kg b.w.) also suppressed the deposition of Ca and P in the aorta, but there was no change due to vitamin K3 or geranylgeraniol (side chain of vitamin K2) administration. Both vitamin K2 and vitamin E showed lipid radical scavenging activity in the in vitro experiment. However, neither vitamin K3 nor geranylgeraniol exhibited anti-arteriosclerotic or radical scavenging activity under the above experimental conditions. It is suggested that vitamin K2 and vitamin E promoted an antiarteriosclerotic effect by radical scavenging activity. These actions of vitamin K2 are required in the structure of 2-methylnaphtoquinone and its side chain (geranylgeraniol).

Topics: Animals; Aorta; Arteriosclerosis; Calcium; Diet, Atherogenic; Elastin; Ergocalciferols; Free Radical Scavengers; Male; Naphthoquinones; Phosphorus; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Vitamin E; Vitamin K; Vitamin K 3

Calcification of extracellular matrix (ECM) can be either physiological or pathological. Physiological calcification (or mineralization) of ECM is restricted to bones, teeth and, to a lesser extent, growth plate cartilages. Pathological calcification appears often in the ECM of arteries where it is a frequent complication of atherosclerosis. However, calcification of the ECM of arteries is not restricted to atherosclerosis. Indeed, human diseases have been described that are characterized by calcification of the aortic media in the absence of any atherosclerotic lesions. The existence of these rare diseases, along with several mouse models recently generated and discussed below, indicates that the formation of atherosclerotic lesions and the calcification of the artery ECM are controlled by different genetic pathways. This emerging knowledge has implications for our understanding of ECM calcification beyond atherosclerosis.

Topics: Animals; Arteries; Arteriosclerosis; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix; Extracellular Matrix Proteins; Glycoproteins; Humans; Matrix Gla Protein; Mice; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases; Vitamin K

Gamma-Carboxyglutamic acid (Gla)-containing protein, synthesized in the presence of vitamin K, has been found in atherogenic plaques, but the pharmacological effect of vitamin K on atherosclerosis is unclear. We examined whether vitamin K2 (menatetrenone) could affect the progression of both atherosclerosis and hypercoagulability in hypercholesterolemic rabbits. Vitamin K2 in daily doses of 1, 10 and 100 mg/kg was given with a 0.5% cholesterol diet for 10 weeks to 8 rabbits each. The plasma levels of total-cholesterol in the vitamin K2-treated groups were clearly lower than that of the hypercholesterolemic control group. The excessive dose of vitamin K2, even at the high dose of 100 mg/kg/day for 10 weeks, did not accelerate the progression of atherosclerosis and did not promote the coagulative tendency in the rabbits. In contrast, the vitamin K2 treatment (1 to 10 mg/kg/day) suppressed the progression of atherosclerotic plaques, intima-thickening and pulmonary atherosclerosis, the increase of ester-cholesterol deposition in the aorta, and both the elevation in plasma factor X level and increase in Hepaplastin test value in the rabbits. These results indicate that the pharmacological dose of vitamin K2 prevents both the progression of atherosclerosis and the coagulative tendency by reducing the total-cholesterol, lipid peroxidation and factor X activity in plasma, and the ester-cholesterol deposition in the aorta in hypercholesterolemic rabbits.

Topics: Animals; Aorta; Arteriosclerosis; Blood Coagulation; Hemostatics; Hypercholesterolemia; Lipid Peroxides; Male; Rabbits; Vitamin K; Vitamin K 2

Protein-bound gamma-carboxyglutamate (Gla) has been demonstrated in calcified atherosclerotic plaques. Vitamin K is required for the formation of Gla-residues. As the biological activity of Gla-proteins appears to be strictly dependent on the presence of the Gla-residues, vitamin K status may be an important factor in the development and progression of atherosclerotic calcifications. We studied the association of vitamin K status, as assessed by nutritional vitamin K intake and the measurements of two circulating immunoreactive osteocalcin (irOC) fractions, with aortic atherosclerosis in a population-based study of 113 postmenopausal women. Women with calcified lesions (n = 34) had a 42.9 micrograms lower mean age-adjusted dietary vitamin K intake/day (95% C.I. -6.6 to 92.5) than those without calcifications (n = 79). Atherosclerotic women had higher irOC levels with a low affinity for hydroxyapatite (irOCfree): age-adjusted difference of 0.32 ng/ml (95% C.I. 0.03 to 0.61). In addition, the high affinity irOC levels expressed as a percentage (hydroxyapatite binding capacity, HBC) were 5.12% (95% C.I. 1.32 to 8.92) lower in women with calcifications. Our study indicates that women with aortic atherosclerosis have an impaired vitamin K status as reflected by a lower nutritional vitamin K intake, an increased irOCfree level and a reduced HBC level. An impaired vitamin K status in subjects with atherosclerosis is compatible with the view that vitamin K or Gla-containing proteins are involved in the development of calcification of the vessel wall.

Topics: 1-Carboxyglutamic Acid; Aged; Aorta, Abdominal; Aortic Diseases; Arteriosclerosis; Body Constitution; Body Mass Index; Calcinosis; Chromatography, Affinity; Cohort Studies; Diet; Durapatite; Female; Humans; Middle Aged; Osteocalcin; Vitamin K; Vitamin K Deficiency

Calcium binding proteins containing gamma-carboxyglutamic acid (Gla) have previously been demonstrated to occur in calcified atherosclerotic plaque and calcified cardiac valves. Experiments were carried out to determine if one of the Gla-containing proteins in human cardiovascular calcifications is the vitamin K-dependent bone protein, osteocalcin. A radio-immunoassay for human osteocalcin was employed, and EDTA extractions of calcified atheromata, and aortic valves as well as relevant noncalcified material were analyzed. Tissue calcium levels were also determined, as were Gla levels as a measure of total vitamin K-dependent protein content. Osteocalcin was present at low levels in all calcified cardiovascular tissues (4.5-175.7 ng osteocalcin/mg protein) with trace levels or nondetectable amounts present in noncalcified tissue. Osteocalcin accounted for a small proportion of the total protein-bound Gla (0.01-0.05%). The relationship of osteocalcin to the other Gla-containing proteins of atherosclerotic plaque including atherocalcin, the principal extractable Gla-containing protein of calcified plaque, is discussed.

Topics: 1-Carboxyglutamic Acid; Adult; Aged; Arteriosclerosis; Bone and Bones; Calcinosis; Calcium-Binding Proteins; Child; Child, Preschool; Glutamates; Heart Valves; Humans; Middle Aged; Osteocalcin; Proteins; Vitamin D; Vitamin K

Topics: 1-Carboxyglutamic Acid; Adult; Aged; Amino Acids; Aorta; Arteriosclerosis; Blood Proteins; Calcium; Calcium-Binding Proteins; Edetic Acid; Female; Glutamates; Humans; Immunodiffusion; Male; Middle Aged; Molecular Weight; Vitamin K

Topics: Anticoagulants; Arteriosclerosis; Drug Evaluation; Humans; Leg; Vasodilator Agents; Vitamin K

Topics: Arteriosclerosis; Female; Humans; Hypertension; Liver Cirrhosis; Male; Neoplasms; Rheumatic Diseases; Vitamin K

Topics: Angina Pectoris; Anticoagulants; Arterial Occlusive Diseases; Arteriosclerosis; Coumarins; Disseminated Intravascular Coagulation; Fibrinolytic Agents; Heparin; Humans; Myocardial Infarction; Pulmonary Embolism; Streptokinase; Thromboembolism; Thrombophlebitis; Thrombosis; Urokinase-Type Plasminogen Activator; Vitamin K

Topics: Arteriosclerosis; Blood Platelets; Coronary Disease; Fibrinolytic Agents; Humans; Myocardial Infarction; Terminology as Topic; Thrombosis; Vitamin K

Topics: Arteriosclerosis; Basal Metabolism; Cholesterol; Dietary Fats; Fatty Acids, Essential; Fatty Acids, Nonesterified; Humans; Lipid Metabolism; Obesity; Triglycerides; Vitamin A; Vitamin D; Vitamin E; Vitamin K

Topics: Aneurysm; Animals; Aortic Aneurysm; Aortography; Arteries; Arteriosclerosis; Arteriosclerosis Obliterans; Blood Coagulation; Blood Vessel Prosthesis; Dextrans; Dicumarol; Dogs; Female; Fibrinolytic Agents; Heparin; Humans; Male; Methods; Nylons; Phenindione; Plastics; Postoperative Complications; Suture Techniques; Thrombosis; Vascular Surgical Procedures; Vitamin K

Topics: Arteriosclerosis; Atrial Fibrillation; Cerebrovascular Disorders; Coronary Disease; Dicumarol; Diet; Diet Therapy; Family Practice; General Practice; Humans; Intracranial Embolism; Intracranial Embolism and Thrombosis; Myocardial Infarction; Prothrombin Time; Thrombosis; Vitamin K; Warfarin

Topics: Animals; Arteriosclerosis; Cholesterol; Lagomorpha; Rabbits; Research; Vitamin A; Vitamin E; Vitamin K; Vitamins

Topics: Arteriosclerosis; Atherosclerosis; Cholesterol; Dietary Fats; Dietary Proteins; Humans; Vitamin K; Vitamins

Topics: Arteriosclerosis; Enzyme Therapy; Enzymes; Hormones; Vitamin A; Vitamin K; Vitamins

Topics: Arteriosclerosis; Coenzymes; Dextrans; Esters; Sulfuric Acid Esters; Vitamin A; Vitamin B 6; Vitamin K; Vitamins

Topics: Arteriosclerosis; Atherosclerosis; Humans; Russia; Vitamin K; Vitamins

Topics: Arteriosclerosis; Blindness; Double-Blind Method; Joints; Vitamin A; Vitamin B 6; Vitamin E; Vitamin K; Vitamins

Topics: Antifibrinolytic Agents; Arteriosclerosis; Atherosclerosis; Fatty Acids, Essential; Humans; Vitamin K

Topics: Arteriosclerosis; Humans; Lipotropic Agents; Vitamin A; Vitamin K; Vitamins

Topics: Arteriosclerosis; Humans; Lipids; Nutritional Status; Proteins; Vascular Diseases; Vitamin K; Vitamins

Topics: Aged; Arteriosclerosis; Humans; Lipotropic Agents; Nutrition Therapy; Vitamin A; Vitamin K; Vitamins

Topics: Arteriosclerosis; Atherosclerosis; Humans; Vitamin A; Vitamin K; Vitamins

Topics: Arteriosclerosis; Humans; Lipid Metabolism; Lipids; Phytol; Retinoids; Vitamin A; Vitamin E; Vitamin K; Vitamins

Topics: Arteriosclerosis; Humans; Iodine; Methionine; Niacin; Nicotinic Acids; Sulfur; Vitamin A; Vitamin E; Vitamin K; Vitamins

Topics: Arteriosclerosis; Vitamin A; Vitamin K; Vitamins

Topics: Androgens; Arteriosclerosis; Estrogens; Vitamin A; Vitamin K; Vitamins