Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperhomocysteinemia is believed to be responsible for the development of vascular disease via several mechanisms, including the impairment of endothelial-cell functionality. In-vitro studies have demonstrated that homocysteine decreases the production or bioavailability of vasodilator autacoids, such as prostacyclin and NO. Here, we show that the treatment of human endothelial cells with noncytotoxic homocysteine concentrations leads to a dose-dependent decrease in both the secretion of the vasoconstrictor agent endothelin-1 (ET-1) and the level of its mRNA. Homocysteine had an inhibitory effect at pathophysiological (0.1 and 0.5 mmol.L(-1)) and pharmacological noncytotoxic (1.0 and 2.0 mmol.L(-1)) concentrations. Mean percentage variation from control for ET-1 production was -36. 2 +/- 18.9% for 0.5 mmol.L(-1) homocysteine and -41.5 +/- 26.8% for 1.0 mmol.L(-1) homocysteine, after incubation for 8 h. Mean percentage variation from control for steady-state mRNA was -17.3 +/- 7.1% for 0.5 mmol.L(-1) homocysteine and -46.0 +/- 10.1 for 1.0 mmol.L(-1) homocysteine, after an incubation time of 2 h. ET-1 production was also reduced by incubation with various other thiol compounds containing free thiol groups, but not by incubation with thiol compounds with no free thiol group. Co-incubation of cells with homocysteine and the sulfhydryl inhibitor N-ethylmaleimide prevented the effect of homocysteine on ET-1 production, confirming a sulfhydryl-dependent mechanism. Based on the reciprocal feedback mechanism controlling the synthesis of vasoactive mediators, these preliminary data suggest a mechanism by which homocysteine may selectively impair endothelium-dependent vasodilation by primary inhibition of ET-1 production.
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PMID:Homocysteine decreases endothelin-1 production by cultured human endothelial cells. 1040 44

An elevated level of total homocysteine (tHcy) in blood-hyperhomocysteinemia, is prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral and peripheral vessels and for thromboembolism (arterial and venous). Elevated total homocysteine confers a graded risk with no threshold, is independent of but may enhance the effect of conventional risk factors. Hyperhomocysteinemia seems to be a particularly strong predictor of cardiovaskular mortality. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe and inexpensive means to reduce an elevated total homocysteine level.
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PMID:[Homocysteine--a routine biochemical parameter in cardiovascular diseases?]. 1042 25

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.
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PMID:Homocysteine metabolism. 1044 23

Hyperhomocysteinaemia is associated with an increased risk of arterial vascular disease and thrombosis in adults. Our aim was to study the association of hyperhomocysteinaemia and stroke in children. Since some patients who had suffered a stroke developed seizures and received treatment with anti-epileptic (antifolate) drugs, we also examined the possible interaction between anti-epileptic drugs and hyperhomocysteinaemia. Plasma total homocysteine was measured in 68 children with stroke (23 of the 68 were taking anti-epileptic drugs) and 100 children undergoing anti-epileptic treatment but without history of stroke, and we compared the values with our reference values for similar ages (n = 195). Total homocysteine was determined by high profile liquid chromatography with fluorescence detection. Hyperhomocysteinaemia was defined as a homocysteine concentration above the 95th percentile for the reference values. Significant differences were found in total homocysteine values of children with stroke and those taking anti-epileptic drugs compared with our reference values for similar ages, except for the adolescent group. Total homocysteine values above the 95th percentile for the reference values were found in 36% of patients with stroke and 28% of children on anti-epileptic treatment. Total homocysteine concentrations in the 23 patients with both stroke and anti-epileptic drug treatment were similar to those of untreated patients with stroke in all age groups. In summary, systematic screening for hyperhomocysteinaemia should be included in the protocol to investigate the aetiology of stroke, even in paediatrics. Anti-epileptic treatment in children with stroke may be responsible for the mild hyperhomocysteinaemia observed in some of them. A dietary supplement of folate may be of benefit in children with stroke and in patients taking anti-epileptic drugs.
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PMID:Evaluation of hyperhomocysteinaemia in children with stroke. 1046 66

The 1996 Bethesda Conference acknowledged left ventricular hypertrophy, hyperhomocysteinemia, lipoprotein(a) excess, hypertriglyceridemia, oxidative stress, and hyperfibrinogenemia as possible new cardiac risk factors. This review summarizes the current literature that supports these conditions as cardiac risk factors. Left ventricular hypertrophy is an independent risk factor for vascular disease. Improvement or progression of left ventricular hypertrophy influences subsequent cardiovascular complications. Clinical trials are under way to assess the potential benefit of decreasing homocysteine levels. The role of lipoprotein(a) excess in vascular disease is controversial. The atherogenic potential of lipoprotein(a) seems to be neutralized by effective reduction of low-density lipoprotein cholesterol levels. Increasing evidence supports an independent role of hypertriglyceridemia in cardiovascular disease and a possible clinical benefit from decreasing triglyceride levels. Among antioxidant micronutrients, supplementation with vitamin E has been shown to be beneficial in primary and secondary prevention studies. Data supporting the use of other antioxidants are much weaker. Preliminary evidence suggests that reducing fibrinogen levels in patients with high baseline levels and coronary disease may be beneficial. Despite the potential relation between new risk factors and cardiovascular disease, routine clinical application of these conditions as cardiovascular risk factors would be premature. Evidence is needed that these conditions extend prognostic ability beyond conventional risk factors and that modification of these conditions can reduce the risk for cardiovascular events.
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PMID:Potential new cardiovascular risk factors: left ventricular hypertrophy, homocysteine, lipoprotein(a), triglycerides, oxidative stress, and fibrinogen. 1078 77

Non-insulin-dependent diabetes mellitus (NIDDM) and hyperhomocysteinemia are both associated with premature vascular disease. We tested the hypothesis that homocysteine is associated with vascular disease and other diabetic complications in patients with NIDDM. The current investigation is a cross-sectional analysis of baseline variables for participants in the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Men and women aged 40 to 74 years with NIDDM and a mean diastolic blood pressure (BP) of 80 mm Hg or higher were eligible. We measured serum levels of total homocysteine (tHcy), cystathionine, and methylmalonic acid (MMA) and correlated these values with clinical and other laboratory measures of the complications of diabetes mellitus in 452 subjects. tHcy was higher in males than in females and correlated with the duration of hypertension and systolic BP. tHcy was significantly correlated with MMA (r = .35, P < .0001) and cystathionine (r = .53, P < .0001) levels and inversely correlated with serum B12 (r = -.23, P < .0001) and folate (r = -.18, P < .0001). It was significantly correlated with serum creatinine (r = .28, P < .0001 for males and r = .39, P < .0001 for females) and inversely correlated with creatinine clearance (r = -.19, P < .005 for males and r = -.30, P < .0001 for females). tHcy was not increased in subjects with cardiovascular disease or retinopathy, but it was increased in those with neuropathy (10.3 v 9.3 micromol/L, P < .05) and macroalbuminuria (11.0 v 9.2 micromol/L, P < .005). Of these subjects, 2.2% met the criteria for vitamin B12 deficiency and 1% met the criteria for folate deficiency. We conclude that elevations of tHcy in this population appear to be the result of a combination of vitamin deficiency and decreased renal function and do not appear to be a predictor of cardiovascular disease.
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PMID:Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus. 1048 47

Increased levels of the physiological amino acid homocysteine (Hcy) are considered a risk factor for vascular disease. Hyperhomocysteinemia causes an intense remodelling of the extracellular matrix in arterial walls, particularly an elastolysis involving metalloproteinases. We investigated the activation of the latent elastolytic metalloproteinase proMMP-2 (72 kDa) by Hcy. Hcy was proved to exert a dual effect, activating proMMP-2 at low molar ratio (MR 10:1) and inhibiting active MMP2 at high molar ratio (MR > 1000:1). Methionine and the disulphide homocystine did not activate nor inhibit MMP-2, showing that the activation as well as the inhibition requires the thiol group to be free. The activation of proMMP-2 by Hcy is in accordance with the "cysteine-switch" mechanism, but occurs without further autoproteolysis of the enzyme molecule. In contrast with Hcy, the other physiological thiol compounds cysteine and reduced glutathione did not activate proMMP-2. These results suggest that the direct activation of proMMP2 by Hcy could be one of the mechanisms involved in the extracellular matrix deterioration in hyperhomocysteinemia-associated arteriosclerosis.
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PMID:Influence of homocysteine on matrix metalloproteinase-2: activation and activity. 1049 21

Hyperhomocysteinemia has been associated with both vascular structure alterations and vascular clinical end points. To assess the relation between plasma homocysteine, structure and function of large arteries, and the presence of clinical vascular disease, we investigated a population of 236 hypertensive patients. We estimated arterial stiffness by measuring the carotid-femoral pulse wave velocity. Total plasma homocysteine was determined by fluorometric high-performance liquid chromatography. The presence of cardiovascular disease was defined on the basis of clinical events, including coronary heart disease, cerebrovascular disease, and peripheral vascular disease. In this population, pulse wave velocity was positively correlated with homocysteine, even after adjustments for age, mean blood pressure, extent of atherosclerosis, and creatinine clearance (P=0.016). Analysis of variance showed statistically significant differences between the mean values of homocysteine, creatinine clearance, and pulse wave velocity according to the extent of atherosclerosis, with an increase in these 3 parameters concomitant with an increase in the number of vascular sites involved with atherosclerosis. In conclusion, in hypertensive patients the levels of homocysteine are strongly and independently correlated to arterial stiffness measured by aortic pulse wave velocity. Plasma homocysteine, creatinine clearance, and aortic pulse wave velocity are higher in patients presenting with clinical vascular disease. These results suggest that the evaluation of aortic distensibility and homocysteine levels can help in cardiovascular risk assessment in hypertensive populations.
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PMID:Plasma homocysteine, aortic stiffness, and renal function in hypertensive patients. 1052 70

The effect of homocysteine-lowering treatment on thrombin generation was investigated in 17 subjects with hyperhomocysteinemia (aged 22-60 years), 11 of whom had symptomatic atherosclerotic vascular disease. All subjects had fasting total homocysteine levels above 16 micromol/L. The formation of thrombin was assessed by measuring thrombin-antithrombin III complexes and prothrombin fragment 1+2 in peripheral venous blood and in the bleeding time blood collected at 30-second intervals from skin incisions on a forearm. All the tests were performed before and after an 8-week treatment with folic acid p.o. 5 mg/day, vitamin B6 p.o. 300 mg/day, and vitamin B12 i.m. 1000 microg given on a weekly basis. Following the 8-week therapy, the median plasma homocysteine concentration became significantly reduced from 20 to 10 micromol/L, while plasma levels of fibrinogen, prothrombin, and antithrombin III as well as activity of protein C, S, and factor VII showed no changes. Vitamin treatment was associated with a significant fall in thrombin-antithrombin III complexes and prothrombin fragment 1+2 concentrations in peripheral venous blood. Bleeding time became prolonged by about 60 seconds. At sites of hemostatic plug formation, plasma concentrations of both thrombin markers significantly decreased. Compared with pretreatment values, significantly less thrombin was produced during the first 3 minutes of bleeding after homocysteine-lowering therapy. In subjects with hyperhomocysteinemia a reduction of plasma fasting homocysteine concentration by folic acid and vitamins B12 and B6 administration is associated with attenuation of thrombin generation both in peripheral blood and at sites of hemostatic plug formation.
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PMID:Treatment of hyperhomocysteinemia with folic acid and vitamins B12 and B6 attenuates thrombin generation. 1052 5

This pictorial introduction to homocysteine illustrates at a glance the nature of homocysteine and its role in cardiovascular disease by means of eight simple figures and an essential bibliography. Homocysteine is a sulfur-containing metabolite of methionine. Conversion back to methionine or transsulfuration to cysteine are the two major metabolic pathways that reduce total homocysteine (tHcy) concentrations in cells and blood. B vitamins are essential cofactors in homocysteine metabolism. Median fasting total homocysteine levels in adult males are approximately 10 micromol/L. Increased plasma tHcy concentrations are found with methionine-rich diets, low vitamin B intake, male gender, age, impaired renal function, and genetically determined defects of the enzymes involved in homocysteine metabolism. An inverse relation exists between plasma tHcy and circulating folate or vitamin B(6) concentrations, and folic acid supplements of 0.5 mg/d can reduce tHcy levels by approximately 25%. Homocystinuric patients, who have severe hyperhomocysteinemia, die prematurely of atherothrombotic disease. Many (but not all) cross-sectional and prospective studies indicate, on average, that plasma tHcy levels <.10 micromol/L are associated with, or predict the development of, coronary, cerebral, and peripheral vascular disease. The risk conferred by hyperhomocysteinemia is graded and is independent of traditional risk factors, with an estimated odds ratio for ischemic heart disease of 1.4 for every 5 micromol/L increase in plasma tHcy. In vitro and in vivo, tHcy has been found to impair endothelial function. It is now well established that tHcy represents a marker of current or subsequent ischemic vascular disease. However, irrefutable proof that hyperhomocysteinemia actually causes atherothrombosis will come only if interventions to lower plasma tHcy will produce concomitant reductions in cardiovascular events.
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PMID:Homocysteine and risk of cardiovascular disease. 1059 Jan 84


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