Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological research has shown that elevated plasma total homocysteine (tHcy) is a risk factor for atherosclerotic disease. In the present case-control study, we investigated whether fasting or postmethionine-loading tHcy was a stronger predictor of risk of severe coronary atherosclerosis. Furthermore, we studied levels of B vitamins, which are involved in homocysteine metabolism. Subjects were recruited from men and women, aged 25 to 65 years, who underwent coronary angiography between June 1992 and June 1994 in a hospital in Rotterdam, The Netherlands. Cases (n=131) were defined as those with > or =90% occlusion in one and > or =40% occlusion in a second coronary artery, while control subjects (n=88) had <50% occlusion in only one coronary vessel. In addition, a population-based control group free from clinical cardiovascular disease (n=101) was studied. Coronary patients were studied at least 2.5 months after angiography or other acute illness, such as myocardial infarction. After adjusting for age and sex differences between the groups, cases had 9% (P=.01) higher geometric mean fasting and 7% (P=.04) higher geometric mean postload tHcy than the combined control groups. Despite higher levels of tHcy for cases, their geometric mean levels of red cell folate and pyridoxal 5'-phosphate were higher than for control subjects, whereas plasma vitamin B12 was only slightly lower in cases. The frequency distribution of tHcy values in cases was slightly shifted toward the right, across the entire range, compared with the distribution in the combined control group. This was somewhat more obvious for fasting than postload tHcy levels. The odds ratio (OR) for severe coronary atherosclerosis (case status) for each 1 SD increase in fasting tHcy (5 micromol/L) was 1.3 (95% confidence interval [CI], 1.0-1.6), similar to the OR for each 1 SD increase (12 micromol/L) in postmethionine-loading tHcy (1.3 [95 CI, 1.0-1.7]), after adjustment for sex, age, and other potential confounders. Furthermore, there was a significant linear trend of increasing fasting tHcy with increasing number of occluded arteries (P=.01), correcting for sex, age, and other potential confounders. Our data show a positive association between plasma tHcy and risk of severe coronary atherosclerosis, of similar strength for fasting and postload tHcy levels. The data suggest that the association exists over a wide range of tHcy levels, without a clear cutoff point below which there is no increased risk.
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PMID:Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. 915 65

We describe a 39-year-old woman with an 8-month history of abdominal pain, diarrhea, and weight loss. Clinical and laboratory evaluation indicated the presence of a malabsorption syndrome. Endoscopy revealed multiple gastric ulcerations and an abnormal "picture" of the duodenal mucosa. At duodenal biopsy, necrosis confined to the distal parts of the enteric villi and a polymorphonuclear leukocyte response were found. Further evaluation revealed intestinal ischemia as a result of mesenteric atherosclerosis. After a revascularization procedure was performed, the symptoms disappeared. The macroscopic and microscopic picture of the bowel normalized. In our search for risk factors of atherosclerosis, we found a substantially increased basal plasma homocysteine concentration. This case suggests that hyperhomocysteinemia may have a causal role in the development of symptomatic, premature atherosclerosis of the mesenteric circulation.
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PMID:Malabsorption syndrome associated with ulceration of the stomach and small bowel caused by chronic intestinal ischemia in a patient with hyperhomocysteinemia. 917 39

Patients with homozygous homocystinuria are at greatly increased risk for development of atherosclerosis and thrombosis (1). Elevated plasma levels of homocysteine (HCY) are caused by reduced enzymatic catabolism or reduced enzymatic remethylation of HCY, due to either hereditary enzyme defects or to nutritional deficiencies of vitamins functioning as cofactors. However, several recent studies have suggested that persons with mildly elevated plasma levels of HCY also are at increased risk for coronary heart disease. (2-4). There are some indications that dietary n-3 polyunsaturated fatty acids (PUFAs) may offer protection against coronary heart disease (5-6). Several mechanisms may be involved, including beneficial effects of n-3 PUFAs on plasma lipids, platelet and leukocyte reactivity, blood pressure and vasoreactivity (7). Interestingly, Olszewski el al. recently found HCY-levels to be lowered 36% in 15 type IIa or IIb hyperlipemic men by n-3 PUFA supplementation. A possible beneficial effect of n-3 PUFA on the incidence of coronary heart disease was initially suggested from studies in Greenland Inuits by our group (8). We therefore investigated plasma levels of homocysteine in a group of traditionally living Greenland Inuits with a diet consisting mainly of marine food and with a very high content of n-3 PUFAs.
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PMID:Homocysteine in Greenland Inuits. 918 21

First recognized in patients with rare inborn errors of metabolism, the association of elevated plasma homocysteine concentrations with atherosclerosis and thrombosis now seems relevant to the general population as well. The mechanism of injury appears to involve oxidative damage to endothelial cells. Vitamin supplementation can normalize homocysteine levels and may lower the incidence of atherothrombotic vascular disease.
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PMID:Homocysteine, oxidative stress, and vascular disease. 927 60

Different fractions (reduced and total) of thiols (homocysteine, cysteine and glutathione) were determined in HeLa cell cultures with and without addition of copper ions and/or homocysteine. In cell cultures without any addition the concentration of all intracellular thiols increased between 1 and 24 h of culture. Glutathione had the highest, whereas homocysteine showed the lowest, proportion of the reduced form. In the medium, there was a decrease of total cysteine during the incubation, but the amount of extracellular reduced cysteine increased. Both homocysteine and glutathione were released into the medium. The amount of exported homocysteine during the incubation exceeded several-fold the intracellular amount. There were no signs of cell toxicity induced by the high amounts of extracellularly added homocysteine (2000 mumol/l) in HeLa cell cultures, except a slight decrease in the concentration of intracellular glutathione. After the addition of copper ions (500 mumol/l) there was a retarded cell growth, decreased intracellular concentration of glutathione, increased release of glutathione into the medium and a lower proportion of all intra- and extracellular reduced thiols. After the addition of both copper ions and homocysteine to HeLa cell cultures, similar changes as with the addition of copper ions were noted except that the cell growth was still more retarded and that a very high level of intracellular homocysteine was noted at 1 h of incubation. N-acetylcysteine lowered, in these experiments, the intracellular accumulation of homocysteine and restored, to some extent, the cell growth. In an endothelial cell line even the presence of 500 mumol/l of homocysteine and 50 mumol/l of copper ions inhibited the cell growth and decreased the cellular level of glutathione. Whilst the levels of homocysteine in our short-time cell culture experiments are higher than the mild hyperhomocysteinemia thought to be atherogenic in humans (20-30 mumol/l), it is conceivable that over a longer time-course (several decades) these lower levels of homocysteine in the presence of copper ions could be sufficient to induce cellular effects similar to those found in the present study, eventually leading to atherosclerosis.
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PMID:The effects of homocysteine and copper ions on the concentration and redox status of thiols in cell line cultures. 920 8

A number of primary and secondary prevention trials, including angiographic studies, have indicated that a decrease in dietary saturated fat and cholesterol produces a decrease in the blood levels of cholesterol and low-density lipoprotein (LDL) cholesterol, leading to a decrease in coronary artery disease (CAD). Increasing evidence indicates that the oxidation of LDL in human beings is atherogenic. Of the three major antioxidants, vitamin E, beta carotene, and vitamin C, the evidence is strongest that vitamin E (at a minimum dose of 100 IU/day) has a strong and independent inverse association with CAD. Selenium and flavonoids also have antioxidant properties, but their association with CAD in human beings is equivocal. Two prooxidants, homocysteine and iron, have been found to be associated with CAD. Blood homocysteine levels can be lowered significantly by an increase in dietary folic acid. Clinical trials are needed to assess expeditiously the effect of antioxidants, particularly vitamin E, and of folic acid on CAD and atherosclerosis. The substitution of monounsaturated fat for saturated fat lowers LDL and makes it less susceptible to oxidation without decreasing high-density lipoprotein (HDL) cholesterol. Studies in transgenic mice indicate that apolipoprotein A-I, the major protein of HDL, may inhibit the oxidation of LDL. Dietary trans fatty acids at the level consumed by many Americans can increase LDL cholesterol and may decrease HDL cholesterol. Individuals who have CAD or have family members who have premature CAD have delayed clearance of dietary fat, as judged by studies of postprandial triglyceride metabolism. The importance of decreasing dietary saturated fat and cholesterol is well established, but a number of other factors appear to influence the risk of CAD significantly and provide important areas for future investigation to improve prevention and treatment through better nutrition.
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PMID:The effect of dietary fat, antioxidants, and pro-oxidants on blood lipids, lipoproteins, and atherosclerosis. 921 65

Vascular disease is a major cause of morbidity and mortality in end stage renal failure patients and cannot be explained entirely by the prevalence of traditional risk factors for atherosclerosis. A high plasma homocysteine concentration, which is a risk factor for vascular disease is found in patients with end stage renal disease. The exact cause for the hyperhomocysteinaemia seen in these patients is unknown, but is probably related to altered renal metabolism of homocysteine. High homocysteine concentrations may also be attributable to a deficiency of folate, vitamin B6 or vitamin B12 although, because of supplementation, these vitamins may be present in high concentrations in renal patients. The occurrence of hyperhomocysteinaemia despite high plasma vitamin concentration could be due to altered metabolism or inhibition of intracellular vitamin activity. A number of studies have now established hyperhomocystinaemia to be an independent risk factor for atherosclerosis in patients with end-stage renal disease. Plasma homocysteine concentrations can be reduced by administration of folic acid either alone or combined with vitamin B12 or vitamin B6. The effects of such reduction on vascular risk in renal failure patients needs further study.
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PMID:Hyperhomocysteinaemia and end stage renal disease. 923 14

Hyperhomocysteinemia has been recognized as an independent risk factor for cerebral, coronary, and peripheral atherosclerosis. To examine the contribution of homocysteine (H[cys]) in the pathogenesis of vascular diseases, we sought to determine whether the H[cys] effect on vascular smooth muscle (VSMC) proliferation is mediated by a specific receptor/transporter or is due to an interaction with growth factors or cytokines. We show that H[cys] induced c-fos and c-myb and increased DNA synthesis and cell proliferation 12-fold in neural crest-derived VSMC (N-VSMC). The H[cys] effect on N-VSMC proliferation is inhibited by Mk-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a glutamate-gated calcium ion channel receptor, and CGS 19755, a competitive antagonist of NMDA-type glutamate receptor. H[cys] stimulates the synthesis of mass amounts of sn-1,2 diacylglycerol, and activates protein kinase C translocation from the nucleus and cytoplasm to cell membranes. Furthermore, protein kinase C inhibitors block the growth effect mediated by H[cys]. These findings indicate that H[cys]-mediated responses are coupled to diacylglycerol-dependent protein kinase C activation. Our results suggest that homocysteine activates a receptor/transporter-like factor in neural crest derived smooth muscle.
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PMID:Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells. 924 Sep 71

Hyperhomocyst(e)inemia, characterized by accelerated atherosclerosis, is believed to induce endothelial cell injury and promote atherothrombosis by supporting the generation of hydrogen peroxide. Earlier observations in our laboratory demonstrated that in vitro nitrosation of homocyst(e)ine (HCY) prevents the generation of hydrogen peroxide. We, therefore, hypothesized that stimulating the production of nitric oxide (NO) by endothelial cells would detoxify HCY by forming the corresponding S-nitrosothiol, S-nitroso-homocysteine. In an attempt to prove this hypothesis, media containing 1 mM L-arginine, 1 microM bradykinin, a known NO agonist, and one of the biologically relevant thiols (HCY, cysteine, or glutathione) at concentrations of 0, 0.05, 0.5 and 5.0 mM were incubated with bovine aortic endothelial cells (BAEC) for 0.5, 1 and 4 h. S-nitrosothiol (RSNO) concentrations were measured by photolysis-chemiluminescence. Nitric oxide synthase (eNOS or isoform 3) activity and Nos 3 steady-state mRNA levels were determined by the conversion of [3H]L-arginine to [3H]L-citrulline and Northern analysis, respectively. Results demonstrate that increasing concentrations of HCY, and not cysteine or glutathione, in the presence of bradykinin at 0.5, 1, and 4 h led to significant (P < 0.05 by ANOVA) time- and dose-dependent increases in RSNO produced by BAEC. Cells exposed to 1 microM calcium ionophore A23187 in the presence of 5.0 mM HCY also produced a time-dependent increase in RSNO compared to control (P < 0.05 by ANOVA). In an attempt to determine if de novo synthesis was occurring, BAEC were treated with bradykinin following a 4 h pretreatment with HCY. Pretreatment with HCY followed by stimulation also led to a time- and dose-dependent increase in RSNO production (P < 0.05 by ANOVA). Using high performance liquid chromatography with electrochemical detection, S-nitroso-homocysteine was identified following treatment of BAEC with HCY and bradykinin. The increase in RSNO production in the presence of bradykinin and HCY at 4 h occurred concomitantly with a 78% increase in eNOS activity and a 58% increase in steady-state Nos 3 mRNA, with no change in Nos 3 mRNA half-life, compared to control. A partial explanation for HCY's unique ability to support an increase in NO production was demonstrated by showing that the t1/2 of HCY in media was greater than that of cysteine or glutathione. These data show that, in the presence of an NO agonist, HCY increases RSNO production in a time- and dose-dependent fashion that is reflected by an increase in eNOS activity and Nos 3 transcription. These results suggest that stimulation of endogenous NO, or provision of an exogenous NO donor, may ameliorate endothelial cell injury and thereby decrease the atherothrombotic risk of hyperhomocyst(e)inemic states.
Atherosclerosis 1997 Jul 25
PMID:Stimulation of endothelial nitric oxide production by homocyst(e)ine. 924 63

Homozygosity for a 677C-->T mutation at the locus that codes for 5,10-methylenetetrahydrofolate reductase (MTHFR), a folate-dependent crucial enzyme in homocysteine metabolism, may render the enzyme thermolabile and less active and has been associated with increased levels of plasma total homocysteine (tHcy). We assessed whether this mutation was associated with increased risk of coronary atherosclerosis and plasma levels of tHcy and furthermore studied whether folate status would modify the associations. Data were collected from subjects with substantial coronary atherosclerosis (> or = 90% occlusion in one and > or = 40% occlusion in a second coronary artery, referred to as cases, n = 131) or virtually no coronary narrowing (referred to as coronary controls, n = 87) and from a population-based control group (n = 100), all residing in the Rotterdam area, The Netherlands. Both males and females, aged 25-65 years were studied. The frequency of homozygosity for the mutation (+/+) in cases (10.0%) did not significantly differ statistically from that observed in coronary controls (11.5%, P = 0.71), population-based controls (7.0%, P = 0.43), or combined control groups (9.1%, P = 0.80). In the overall group (as well as in the three subgroups), plasma tHcy levels, fasting and to a lesser extent after a methionine-loading test, were higher in +/+ subjects than in homozygous normal subjects (-/-), whereas heterozygous subjects (+/-) had intermediate levels (Ptrend = 0.001). The +/+ subjects with erythrocyte folate levels < 790 nmol/l (population median) had a 77%, (95% CI, 27-144%) higher geometric mean fasting tHcy (21.4, micromol/l) than those with higher erythrocyte folate (12.1 micromol/l). The odds ratio (OR) of coronary atherosclerosis for +/+ subjects, with +/- and -/- subjects as the reference group, in analyses with combined control groups, was 1.1 (95% CI, 0.5-2.4). The ORs were 2.2 (95% CI, 0.7-6.8) and 0.6 (95% CI, 0.2-1.7) among subjects with low and high folate levels, respectively. Our study indicates that homozygosity for the 677C-->T MTHFR mutation, especially in combination with low folate status, predisposes to high plasma levels of fasting tHcy. However, homozygosity for this mutation, whether or not in combination with low folate status, was not associated with increased risk of coronary artery disease.
Atherosclerosis 1997 Jul 11
PMID:The 677C-->T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. 924 65


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