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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelial surface plays an important role in the pathogenesis of atherosclerosis and the regulation of coagulation. It has become increasingly clear that while perturbed endothelial cells generate procoagulant activity, under normal conditions they possess multiple antithrombotic and anticoagulant mechanisms, including generation of prostacyclin and plasminogen activators and synthesis of thrombomodulin as a cell surface cofactor for thrombin-catalyzed activation of protein C. In addition, anticoagulantly active heparan sulfate proteoglycans, including heparin-like molecules are apparently present on the vascular surface. Previous studies showed that homocysteine, a thromboatherogenic and atherogenic agent, inhibits an endothelial thrombomodulin-protein C anticoagulant pathway. We examined whether homocysteine might affect another endothelial anticoagulant mechanism; i.e., heparin-like glycosaminoglycan-antithrombin III interactions. Incubations of cultured endothelial cells with homocysteine reduced the amount of antithrombin III bound to the cell surface in a dose- and time-dependent fashion. In contrast with a marked reduction in the maximal antithrombin III binding capacity, the radioactivity of [35S] sulfate incorporated into heparan sulfate on the cell surface was minimally reduced. Although neither net negative charge nor proportion in total glycosaminoglycans of cell surface heparan sulfate was altered by homocysteine treatment, a substantial reduction in antithrombin III binding capacity of heparan sulfate isolated from homocysteine-treated endothelial cells was found using both affinity chromatography and dot blot assay techniques. The antithrombin III binding activity of endothelial cells decreased after preincubation with homocysteine, cysteine, or 2-mercaptoethanol, containing a sulfhydryl group; no reduction in binding activity was observed after preincubation with methionine, alanine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Heparan sulfate proteoglycan of endothelial cells: homocysteine suppresses anticoagulant active heparan sulfate in cultured endothelial cells]. 817 41

The atherogenic properties of homocysteine were discovered by observation of arteriosclerosis in children with homocystinuria caused by inherited deficiency of three different enzymes. Hyperhomocysteinemia is generally recognized as an independent risk factor for coronary, cerebral, and peripheral atherosclerosis. Hyperhomocysteinemia is caused by heterozygosity for homocystinuria, micronutrient deficiency from dietary imbalance, toxins, drugs, hormones, and other factors, explaining many key observations concerning the epidemiology of atherosclerosis. The etiological factors for atherosclerosis are believed to increase conversion of methionine to homocysteine thiolactone, the reactive cyclic internal lactone of homocysteine. The free amino groups of low density lipoprotein (LDL) are thiolated by homocysteine thiolactone, causing aggregation and increased uptake of LDL by macrophages, explaining lipid deposition in atheromas. Homocysteine thiolactone, released from homocysteinylated LDL within vascular wall, promotes intimal injury, oxidation of cholesterol and unsaturated lipids, platelet aggregation, thrombogenic factors, myointimal hyperplasia, deposition of sulfated glycosaminoglycans, fibrosis and calcification of atherosclerotic plaques.
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PMID:Chemical pathology of homocysteine. I. Atherogenesis. 829 2

It has been postulated that the accumulation of homocysteine in plasma may induce arteriosclerosis. In order to explore the possible contribution of homocysteine to the occurrence of macroangiopathy in patients with non-insulin-dependent diabetes mellitus, the concentrations of total homocysteine in plasma were determined in 52 diabetic patients with clinical macroangiopathy, 84 diabetic patients without macroangiopathy, and 57 non-diabetic control subjects. The levels of total homocysteine in plasma were significantly higher in diabetic patients with macroangiopathy (10.8 +/- 3.8 nmol/ml) than in those without macroangiopathy (8.3 +/- 3.1 mmol/ml, P < 0.001) or non-diabetic subjects (7.5 +/- 2.1 nmol/ml, P < 0.001). Among all diabetic patients, multiple logistic regression analysis after adjustment for age, sex, and systolic blood pressure revealed that high levels of plasma homocysteine were significantly associated with the presence of diabetic macroangiopathy (P = 0.01). By an intramuscular injection of 1000 micrograms methylcobalamin daily for 3 weeks, the plasma levels of homocysteine in 10 diabetic patients were significantly decreased (14.7 +/- 7.5 vs. 10.2 +/- 6.0 nmol/ml, P < 0.01). Our results suggest that plasma homocysteine levels could be one of a number of independent risk factors for macroangiopathy in patients with diabetes mellitus and that they can be reduced by parenteral treatment with methylcobalamin.
Atherosclerosis 1993 Nov
PMID:Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment. 829 92

Altered homocysteine metabolism is implicated as a pathogenic factor in atherogenesis, neoplasia, and aging. Hereditary enzymatic deficiencies and nutritional deficiencies of folate, pyridoxine, or cobalamin are associated with elevated blood homocysteine, accelerated atherosclerosis, and manifestations of aging. The failure of malignant cells to metabolize homocysteine thiolactone to sulfate is attributed to deficiency of thioretinaco, a complex containing cobalamin, homocysteine thiolactone, and retinoic acid. The sulfhydryl group of homocysteine is believed to act catalytically with ferric or cupric ions in a mixed function oxidation system to generate hydrogen peroxide, oxygen radicals, and homocysteinyl radicals. These reactive species may interact with the active site of enzyme protein to cause inactivation of catalytic activity. Homocysteine thiolactone is oxidized to sulfate by a process involving ascorbate, thioretinamide, and superoxide, under the control of thyroxine and growth hormone. Thioretinaco is believed to be the active site of adenosine triphosphate (ATP) binding in oxidative phosphorylation with the participation of oxygen, ascorbate, proton gradient, and electron transport. Depletion of thioretinaco from mitochondrial and microsomal membranes may be associated with increased formation and release of radical oxygen species within neoplastic and senescent cells. Specific proposals are made for investigating the importance of homocysteine metabolism in the oxidative modification of proteins and lipids.
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PMID:Homocysteine metabolism and the oxidative modification of proteins and lipids. 832 40

Moderate hyperhomocysteinemia may be a risk factor for atherosclerotic peripheral vascular disease (PVD). In order to develop PVD at an early age risk factors are more strongly expressed and hyperhomocysteinemia may be one such factor. Homocysteine is derived from methionine and is metabolised by cystathionine-synthase to cystathionine or remethylated to methionine. Cystathionine-synthase activity is dependent on vitamin B6 while the remethylation of homocysteine is dependent on vitamin B12 and folate. The present study analyses homocysteine in patients operated on for lower extremity ischaemia before the age of 50. Homocysteine before and after loading with methionine, vitamin B6, B12 and folate were measured at follow-up. The patients were compared to age- and sex-matched controls. Significantly more patients than controls had hyperhomocysteinemia, 16/58 vs. 4/65, defined as fasting total homocysteine above 18.6 mumol/l. Loading with methionine did not further discriminate between patients and controls. Smoking patients had higher levels of homocysteine than non-smoking patients or smoking and non-smoking controls. Smoking patients also had lower levels of vitamin B6. When comparing patients with suprainguinal, infrainguinal and multilevel disease the highest homocysteine levels were seen in the latter group. Also, in this group smoking patients had higher homocysteine levels. Multivariate analysis revealed that homocysteine was associated with low levels of vitamin B12, folate and smoking. Smoking therefore seems to be connected to increased homocysteine levels in patients with early development of atherosclerosis, partly explained by decreased levels of B6, B12 and folate.
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PMID:Hyperhomocysteinemia in patients operated for lower extremity ischaemia below the age of 50--effect of smoking and extent of disease. 835 94

Elevated levels of homocysteine are associated with an increased risk of atherosclerosis and thrombosis. The reactivity of the sulfhydryl group of homocysteine has been implicated in molecular mechanisms underlying this increased risk. There is also increasingly compelling evidence that thiols react in the presence of nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) to form S-nitrosothiols, compounds with potent vasodilatory and antiplatelet effects. We, therefore, hypothesized that S-nitrosation of homocysteine would confer these beneficial bioactivities to the thiol, and at the same time attenuate its pathogenicity. We found that prolonged (> 3 h) exposure of endothelial cells to homocysteine results in impaired EDRF responses. By contrast, brief (15 min) exposure of endothelial cells, stimulated to secrete EDRF, to homocysteine results in the formation of S-NO-homocysteine, a potent antiplatelet agent and vasodilator. In contrast to homocysteine, S-NO-homocysteine does not support H2O2 generation and does not undergo conversion to homocysteine thiolactone, reaction products believed to contribute to endothelial toxicity. These results suggest that the normal endothelium modulates the potential, adverse effects of homocysteine by releasing EDRF and forming the adduct S-NO-homocysteine. The adverse vascular properties of homocysteine may result from an inability to sustain S-NO formation owing to a progressive imbalance between the production of NO by progressively dysfunctional endothelial cells and the levels of homocysteine.
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PMID:Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. 838 Aug 12

Normal blood fluidity and perpetuation of the non-thrombogenic state are primarily maintained by the anticoagulant and fibrinolytic systems of vascular endothelial cells involving heparin-like molecule, thrombomodulin, prostacyclin, and the receptor for tissue plasminogen activator. Atherosclerosis perturbes these activities, resulting in arterial thrombosis. On the other hand, recent experimental evidence suggests that the disordered thromboregulation often promotes atherosclerosis. Several known risk factors for development of atherosclerosis, including homocysteine and lipoprotein (a) perturb anticoagulant and fibrinolytic systems of vascular endothelial cells at an early stage of atherogenesis.
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PMID:[Coagulation and fibrinolytic systems and atherogenesis]. 841 63

Intracellular protein transport in endothelial cells is selectively inhibited by homocysteine, a thiol amino acid associated with both thrombosis and atherosclerosis. In a previous study, homocysteine decreased cell surface expression of the surface transmembrane glycoprotein thrombomodulin without decreasing secretion of another endothelial cell protein, plasminogen activator inhibitor-1. To define further the effects of homocysteine on protein transport, we examined the processing and secretion of the multimeric glycoprotein von Willebrand factor (vWF) in human umbilical vein endothelial cells. Incubation with 2 mmol/L homocysteine resulted in complete loss of vWF multimers and prevented asparagine-linked oligosaccharide maturation, propeptide cleavage, and secretion; these effects are consistent with impaired exit from the endoplasmic reticulum (ER). Dimerization was only partially inhibited, suggesting that homocysteine causes retention of provWF in the ER without preventing dimer formation. In pulse-chase incubations, intracellular provWF was degraded before exiting the ER in homocysteine-treated cells. Homocysteine also inhibited the processing and secretion of a carboxyl-terminal truncation mutant of human provWF expressed in rat insulinoma cells, indicating that retention in the endoplasmic reticulum can be mediated by regions of provWF apart from the carboxyl-terminal 20-Kd segment. These results suggest that retention of secretory proteins in the ER is regulated by redox mechanisms and imply that the intracellular transport of multiple endothelial cell proteins may be altered in patients with homocystinuria.
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PMID:Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. 842 60

Elevated plasma homocysteine levels are recognized as an independent risk factor for atherosclerotic disease. It is not known (1) whether the severity of atherosclerotic disease is related to hyperhomocyst(e)inemia or (2) whether any such relation differs between fasting and post-methionine loading plasma homocysteine levels. Therefore, in 171 consecutive patients under 55 years of age with first symptoms of lower-limb disease, we examined the relation between severity of atherosclerosis and plasma homocysteine concentration. Severity of atherosclerotic disease was estimated from the prevalence of coronary artery disease and cerebrovascular disease and from the angiographic extent of lower-limb disease. Plasma homocysteine was measured after a period of fasting and in response to methionine loading (0.1 g/kg). In multivariate analysis, the prevalence of coronary artery disease plus cerebrovascular disease was related to both fasting and postmethionine homocysteine levels (odds ratio [OR] for the upper quartile versus the lower three quartiles, 2.8, 95% confidence interval [CI], 1.1 to 7.5; and OR 3.0, 95% CI, 1.1 to 7.8, respectively). The extent of lower-limb disease was weakly related to the fasting homocysteine level (partial correlation coefficient, .12; P = .17) and more strongly related to the postmethionine homocysteine level (partial correlation coefficient, .25; P = .003). These relations tended to be more pronounced in women than in men. They were independent of age, total serum cholesterol, blood pressure, and smoking habit. We concluded that the severity of atherosclerotic disease in young patients with lower-limb atherosclerotic disease is associated with high postmethionine and fasting homocysteine concentrations.
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PMID:Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. 854 18

The effects of a high level of methionine on the changes of lipid and amino acid metabolism were investigated. Eighteen New Zealand White rabbits were divided into three groups; a methionine group, which was fed a diet supplemented with 3% D, L-methionine, a Cholesterol+Methionine group, which was fed a 3% D, L-methionine and a 0.2% cholesterol diet, and a Cholesterol group which was fed a 0.2% cholesterol diet for 22 weeks. The plasma triglyceride, cholesterol, homocysteine, cysteine and serum SO4(2-) levels were measured and compared. On the first and the final day of the experiment, lipid peroxide levels in blood samples were also measured. We found that the Methionine group and the Cholesterol+Methionine group showed elevated levels of plasma triglyceride, cholesterol, homocysteine, cysteine, serum SO4(2-) and lipid peroxide compared with the Cholesterol group. More prominent fat deposits in the aorta were observed in the Methionine group and the Cholesterol+Methionine group than in the Cholesterol group. Our results indicated that the interaction of cholesterol with methionine or its derivatives plays a role in the progression of atherosclerosis.
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PMID:[The influence of methionine and its metabolites on the progression of atherosclerosis in rabbits]. 855 Aug 5


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