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

Hyperhomocysteimia, either fasting or after oral methionine loading, appears to be an independent risk factor for coronary heart disease (CHD). It remains unclear whether fasting total homocysteine determination alone adequately detects the full spectrum of hyperhomocysteinemic individuals. We measured fasting and 4-h post methionine loading (0.1 g L-methionine/kg body weight) total plasma homocysteine in 274 participants in The NHLBI Family Heart Study, a population-based investigation of genetic and non-genetic determinants of CHD. Of the total number (n = 47) of hyperhomocysteinemic persons, 43% (20/47) were identified only by methionine loading, while 32% (15/47) of the total number, and 75% of those with post-methionine loading hyperhomocysteinemia only (15/20), had fasting total homocysteine concentrations below the 75th percentile (10.7 mumol/l). We conclude that fasting total plasma homocysteine determination alone fails to identify a sizable percentage (> 40%) of persons who may have clinically relevant hyperhomocysteinemia post methionine loading.
Atherosclerosis 1995 Jul
PMID:Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. 748 29

This study shows that the intracellular concentration of homocysteine in cultured cells is kept low due to an accumulation in the medium. The intracellular level of homocysteine was decreased when its precursor, methionine, was omitted from the culture medium. Intracellular glutathione and cysteine were lowered in cystine-deficient medium. Intracellular glutathione was also lowered when copper ions were added to the culture medium. It is evident from this study that the intracellular concentration of homocysteine was not influenced by the lowered level of glutathione and/or cysteine. High amounts of homocysteine added to the medium give rise to an increase of intracellular reduced homocysteine, which participates in the transsulfuration pathway and can replace cysteine in the synthesis of glutathione. The addition of relatively high amounts of reduced homocysteine (500 mumol/l) in the presence of copper ions (100 mumol/l) to the culture medium can be directly toxic to the cells, possibly due to oxygen radicals formed by thiol auto-oxidation. Whilst the level of homocysteine in this study using short-time cell culture experiment is much higher than the mild hyperhomocysteinemia thought to be atherogenic in humans, it is conceivable that over a longer time course these levels of homocysteine could be sufficient to induce endothelial dysfunction, eventually leading to atherosclerosis.
 ...
PMID:Metabolism of homocysteine, its relation to the other cellular thiols and its mechanism of cell damage in a cell culture line (human histiocytic cell line U-937). 757 72

There is increasing evidence that a raised blood level of homocysteine (HC) is a risk factor for premature atherosclerosis. With a gene frequency between one in 70 and one in 200 this condition may be more common than previously thought. It should be suspected especially in young patients in whom other risk factors are absent. The diagnosis may be made by demonstrating raised plasma HC levels, either basally or after methionine loading. Studies have shown significantly increased levels of HC in patients with premature coronary artery, peripheral vascular and cerebrovascular disease. The mechanisms by which HC produces vascular damage are, as yet, not completely understood but endothelial injury is probably a central factor. The principle of treatment is to lower HC levels in the blood by administration of vitamin B6, vitamin B12, folate or betaine. How effective this strategy will be in preventing complications is not yet known.
 ...
PMID:Homocysteine and vascular disease. 762 98

Methionine is converted by the transmethylation/transsulfuration pathway to homocysteine which may exert atherogenic effects by several mechanisms, including lipid peroxidation. Therefore, the excessive dietary methionine may induce the development of atherosclerosis. To test this hypothesis, plasma and aortic thiobarbituric acid reactive substances (TBARS), as well as activities of aortic and erythrocyte superoxide dismutase (SOD), catalase and selenium-dependent glutathione peroxidase (GPX) were measured in rabbits fed a diet enriched with 0.3% methionine for 6 or 9 months. Histological examinations of aortas also were performed. Feeding rabbits a methionine-enriched diet for 6 or 9 months resulted in significant increases in plasma and aortic TBARS levels and aortic antioxidant enzyme activities. However, a decrease in plasma antioxidant activity (AOA) was observed. In erythrocytes, SOD activity increased, catalase remained normal and GPX decreased in the treated animals. Histological examination of aortas showed typical atherosclerotic changes, such as intimal thickening, deposition of cholesterol, and calcification in methionine-fed rabbits. These results confirm that high-methionine diet may induce atherosclerosis in rabbits and indicate disturbances in lipid peroxidation and antioxidant processes as possible mechanisms of its atherogenic influence.
Atherosclerosis 1995 Jun
PMID:Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits. 766 80

Oversecretion of apoB and decreased removal of apoB-containing lipoproteins by the liver results in hyperapobetalipoproteinemia, which is a risk factor for atherosclerosis. We investigated how dexamethasone, a synthetic glucocorticoid, affects the synthesis, degradation, and secretion of apoB-100 and apoB-48. Primary rat hepatocytes were incubated with dexamethasone for 16 hours. Incorporation of [35S]methionine into apoB-48 and apoB-100 was increased by 36% and 50%, respectively, with 10 nmol/L dexamethasone, despite a 28% decrease of incorporation into total cell proteins. However, Northern blot analysis revealed that dexamethasone (1 to 1000 nmol/L) did not significantly alter the steady-state concentrations of apoB mRNA, suggesting that the net increase in apoB synthesis may involve increased translational efficiency. The intracellular retention and the rate and efficiency of apoB secretion were determined by pulse-chase experiments in which the hepatocytes were labeled with [35S]methionine for 10 minutes or 1 hour, and the disappearance of labeled apoB from the cells and its accumulation in the medium were monitored. Degradation of labeled apoB-100 after a 3-hour chase in both protocols was decreased from about 50% to 30%, whereas degradation of apoB-48 was decreased from 30% to 10% to 20% by treatment with 10 or 100 nmol/L dexamethasone. Additionally, the half-life of decay (time required for 50% of labeled cell apoB-100 to disappear from the peak of radioactivity following a 10-minute pulse) was increased by treatment with 10 nmol/L dexamethasone from 77 to 112 minutes, and the value for apoB-48 increased from 145 to 250 minutes. Treatment with 100 nmol/L dexamethasone also stimulated secretion of 35S-labeled apoB-100 and apoB-48 by twofold and 1.5-fold, respectively. The increased secretion of apoB-100 and apoB-48 after dexamethasone treatment was confirmed by immunoblot analysis for apoB mass, and the effect was relatively specific since albumin secretion was not significantly changed. We conclude that glucocorticoids promote the secretion of hepatic apoB-containing lipoproteins by increasing the net synthesis of apoB-100 and apoB-48 and by decreasing the intracellular degradation of newly synthesized apoB. An increased action of glucocorticoids coupled with a decreased ability of insulin to suppress these effects in insulin resistance can lead to hyperapobetalipoproteinemia and an increased risk of atherosclerosis.
 ...
PMID:Effects of dexamethasone on the synthesis, degradation, and secretion of apolipoprotein B in cultured rat hepatocytes. 767 Sep 64

DNA screening for apolipoprotein (apo) B mutations causing familial defective apolipoprotein B-100 (FDB) was performed in 87 hyperlipidemic Belgian individuals using heteroduplex analysis. Eighteen FDB heterozygotes from 5 unrelated families were identified. Three of the index cases reported an early family history of premature coronary heart disease (CHD). The frequency of the apo B3500 mutation was 8% in Belgians with type IIa hyperlipidemia, indicating that the prevalence of FDB may be as high as 1 in 250 in the general Belgian population. Plasma lipid levels of the patients identified in the present study are similar to those previously reported for FDB heterozygotes. We compared these data with results obtained in a genotype/phenotype correlation study of heterozygous familial hyper-cholesterolemia (FH) in the Afrikaner population of South Africa. Plasma cholesterol levels in FDB heterozygotes were similar to those reported for FH heterozygotes with defective receptors (Asp206-->Glu, approximately 20% normal receptor activity), but significantly lower than in FH heterozygotes with a mutant protein which virtually lacks receptor activity (Val408-->Met, < 2% normal receptor activity). FDB appears to be a significant genetic cause of hypercholesterolemia in Belgium.
Atherosclerosis 1994 Dec
PMID:Phenotypic expression and frequency of familial defective apolipoprotein B-100 in Belgian hypercholesterolemics. 771 24

Lipoprotein lipase (LPL), which is secreted by the two predominant cell types in atherosclerotic plaque, macrophages and smooth muscle cells, may be involved in atherosclerosis by generating atherogenic remnant lipoproteins. We investigated the effects of platelet-derived growth factor (PDGF)-BB on the synthesis of LPL by human monocyte-derived macrophages. These cells were cultured in the presence of PDGF-BB for 8 days, after which the enzyme activity, mass, and mRNA levels of LPL were determined. The effect of PDGF-BB was time-dependent and dose-dependent at concentrations of 1 to 10 ng/mL. At 10 ng/mL PDGF-BB enhanced twofold to 2.3-fold the secretion of LPL, and a pulse-labeling study with [35S]methionine revealed that 10 ng/mL PDGF-BB significantly increased the synthesis of LPL. Northern blotting analysis showed that the LPL mRNA level increased dose dependently in macrophages treated with PDGF-BB, and 10 ng/mL PDGF-BB enhanced twofold the expression of LPL mRNA. The protein kinase C inhibitor staurosporine suppressed the effect of PDGF-BB on LPL activity. These results indicate that PDGF-BB stimulated transcription of the LPL gene in human monocyte-derived macrophages through protein kinase C activation and resulted in an increased synthesis of LPL. Therefore, we hypothesize that the augmented synthesis of LPL by PDGF-BB modulates atherosclerosis by influencing lipoprotein metabolism in the vascular wall.
 ...
PMID:Effects of platelet-derived growth factor on the synthesis of lipoprotein lipase in human monocyte-derived macrophages. 774 65

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.
 ...
PMID:Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. 778 64

Homocysteine (HCY), which is derived from the intracellular metabolism of methionine, is exported into plasma, where it circulates mostly in oxidized forms (i.e., homocystine and cysteine-HCY disulfide) and mainly bound to proteins. Concentrations of total HCY, or homocyst(e)ine [H(e)], are increased in 15-40% of patients with coronary, cerebral, or peripheral arterial diseases. Such association of H(e) with arterial occlusive diseases has been documented in retrospective, cross-sectional, and prospective studies. Concentrations of H(e) are also increased in subjects having thickened carotid arteries, as determined by ultrasonography, and who are asymptomatic for atherosclerosis. Statistical analyses of data from several series of patients demonstrate that H(e) concentrations are associated with coronary artery disease, independently from most other risk factors for atherosclerosis. The increased concentrations of H(e) are readily corrected by folic acid, occasionally supplemented with pyridoxine, vitamin B12, choline, or betaine. Whether these supplements affect the evolution of atherosclerotic disease needs to be established by prospective, placebo-controlled clinical trials.
 ...
PMID:Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review. 781 76

The aim of this study was to determine the prevalence of hyperhomocysteinaemia in cardiac transplant recipients. Three groups of subjects were studied: 27 heart transplant recipients, 14 to 63 months (mean = 36.5) after transplantation; 10 patients with moderate chronic renal insufficiency without clinical evidence of vascular disease; 17 apparently healthy individuals. Twenty-five out of 27 transplanted patients had a coronaroangiography within 6 months of homocysteine measurement. Plasma homocysteine was measured both while the subject was fasting (t0) and 6 h after administration of 0.1 g.kg-1 of methionine (t6). Hyperhomocysteinaemia was present in 14/27 fasting transplanted patients and after methionine loading. Mean plasma levels of homocysteine at t0 were higher (P = 0.03) in transplanted heart recipients (15.4 +/- 7 mumol.l-1) than in the renal patients (9.9 +/- 5 mumol.l-1) despite similar mean plasma creatinin. In eight transplanted patients with angiographic coronary abnormalities of the cardiac graft, homocysteinaemia was at t0 17.1 +/- 9 mumol.l-1 and at t6 47.8 +/- 25 mumol.l-1. In 17 transplanted patients with angiographically normal coronary arteries, plasma homocysteine levels were at t0, 13.2 +/- 4 mumol.l-1 and at t6, 46.8 +/- 25 mumol.l-1. We conclude that hyperhomocysteinaemia is common in transplanted heart recipients, and partly related to renal insufficiency. No correlation was found between hyperhomocysteinaemia and angiographic evidence of coronary atherosclerosis of the graft, but the population of the study was possibly too small to establish this correlation.
 ...
PMID:Hyperhomocysteinaemia in heart transplant recipients. 798 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>