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)

Cardiovascular disease is the leading cause of mortality in Mexico, as well as in other Western countries. Conventional risk factors for atherosclerosis, such as cigarette smoking, systemic hypertension, diabetes mellitus, and hypercholesterolemia, do not explain this association completely. Recently, it has been recognized that hyperhomocysteinemia contributes to the atherosclerotic process, promoting endothelial damage and oxidative stress in the vascular wall. Homocysteine, an amino acid generated under physiologic conditions after ingestion of protein-rich foods, is used in a variety of metabolic pathways. Elevated plasma levels of this amino acid (higher than 15 mmol/L or lower in the presence of other cardiovascular risk factors) promote the development of atherosclerosis. Folic acid and vitamin B6 and B12 supplements decrease plasma levels of homocysteine effectively and may play an important role in the prevention and treatment of atherosclerotic vascular disease.
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PMID:[Hyperhomocysteinemia. A new coronary risk factor]. 1151 57

Homocysteine is an emerging new risk factor for cardiovascular disease. It is a thiol compound derived from methionine and involved in two main metabolic pathways: the cycle of activated methyl groups, requiring folate and vitamin B12 as cofactors, and the transsulfuration pathway to cystathionine and cysteine requiring vitamin B6 as cofactor. The homocysteine metabolism represents an interesting model of gene-environment interaction. Elevations in homocysteine may be caused by genetic defects in enzymes involved in its metabolism or by deficiencies in cofactor levels. A common polymorphism in the gene coding for the 5,10-methylene tetrahydrofolate reductase (MTHFR) (C677T, Ala --> Val) is associated with a decreased activity of the enzyme due to thermolability. In case of homozygosity for the Val allele, a relative deficiency in the remethylation process of homocysteine into methionine leads to a mild-to-moderate hyperhomocysteinemia, a condition recognized as an independent risk factor for atherosclerosis. The genetic influence of the MTHFR polymorphism on homocysteine levels is attenuated in females in premenopausal age and is not significant in subjects who exhibit serum levels of folate and/or vitamin B12 above the 50th percentile of distribution in the general population. The prevalence of the Val/Val genotype varies among different ethnic groups. It is very low in African populations, whereas in Europe and North America it ranges between 5% and 15%. In Italy an even higher prevalence has been reported in some regions. The question whether the MTHFR polymorphism might be per se an independent contributor to cardiovascular risk is debated. The interaction between this or other genetic factors and environmental/nutritional conditions (i.e. intake of vitamins such as folate) is a key determinant for homocysteine concentrations in healthy conditions as well as in some disease (i.e. in renal disorders). Another example of gene/environment interaction in the field of atherosclerosis is given by the apolipoprotein E polymorphism and its influence in response to diet. The presence of a high prevalence of risk-related allelic variants of such candidate genes within a certain population could serve to locally reinforce the recommendations concerning nutrient intake.
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PMID:MTHFR gene polymorphism, homocysteine and cardiovascular disease. 1168 44

Hyperhomocysteinemia is a significant risk factor in atherosclerosis and thrombosis. However, its role in the development of intimal hyperplasia after arterial reconstructive procedures remains uncertain. We therefore studied the effect of homocysteine on intimal hyperplasia in a rat model of carotid artery balloon injury. Twenty-four Sprague-Dawley rats were divided into three groups: control (saline infusion), and low dose (0.14 mg/day) and high dose (0.71 mg/day) homocysteine delivered continuously via osmotic pumps implanted intraperitoneally. All animals underwent left common carotid artery balloon denudation with sacrifice after 14 days. Plasma homocysteine levels, intimal hyperplasia, and cell proliferation of rat carotid arteries were determined. In vitro rat smooth muscle cell (SMC) proliferation with homocysteine treatment was also performed. Plasma homocysteine levels at sacrifice were 1.80+/-0.35, 2.65+/-0.05 and 3.50+/-0.22 microM in three groups, respectively. Intimal hyperplasia developed in all balloon-injured arteries in both control and homocysteine-treated animals. The intimal area and intima/media area ratio were increased by 92% (P<0.05) and 105% (P<0.05), respectively, in the high dose-homocysteine-treated animals as compared to the control animals. Homocysteine (high dose) also significantly promoted the intimal cell proliferation (bromodeoxyuridine incorporation) by 2.2-fold as compared to controls. Furthermore, homocysteine treatment in the cell culture study showed a concentration-dependent increase of rat SMC proliferation. These data demonstrate that the continuous intraperitoneal administration of homocysteine significantly increases intimal hyperplasia and SMC proliferation after carotid artery balloon injury in the rat as well as in vitro SMC proliferation. This study suggests that, following arterial reconstructive procedures, elevated plasma homocysteine may increase the complications of clinical restenoses that are associated with intimal hyperplasia.
Atherosclerosis 2002 Jan
PMID:Intraperitoneal infusion of homocysteine increases intimal hyperplasia in balloon-injured rat carotid arteries. 1175 27

Homocysteine (tHcy) is a risk factor for atherosclerosis in patients with end-stage renal disease and chronic renal insufficiency (CRI). Vitamin B6 deficiency may result in high tHcy levels, especially after a methionine load (PML). Therefore, we evaluated vitamin B6 metabolism and tHcy (fasting and PML) levels in patients with CRI and those on hemodialysis (HD) therapy before and during high-dose sequential vitamin B6 and folic acid supplementation in male patients (27 patients, HD, 17 patients, CRI) and 19 age-matched healthy controls. Vitamin B6 doses were 100 mg/d in patients with CRI and 200 mg/d in HD patients, plus folic acid (5 mg/d), for more than 3 months in each period. We analyzed vitamin B6 metabolites by high-performance liquid chromatography in plasma and red blood cells (RBCs) and fasting tHcy in all cases and PML in subgroups of 11 HD patients and 14 patients with CRI. We found vitamin B6 deficiency and high tHcy (fasting and PML) levels in all patients. Plasma and RBC levels of pyridoxal and pyridoxal phosphate were abnormally low, whereas levels of pyridoxic acid (PA), an end product of vitamin B6 metabolism, were extremely high in both groups. Fasting and PML tHcy levels were partially resistant to vitamin B6 supplements, with different response patterns in HD patients and those with CRI. Thus, the PML defect was more responsive to folic acid in HD patients, whereas vitamin B6 partially reduced PML tHcy levels in patients with CRI. Resistance of tHcy to vitamin B6 treatment in patients with CRI and HD patients is not caused by poor absorption or low tissue stores. Rather, nonvitamin factors or potentially toxic PA levels may be implicated in abnormal vitamin B6 and/or tHcy metabolism during renal insufficiency.
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PMID:Vitamin B6 metabolism and homocysteine in end-stage renal disease and chronic renal insufficiency. 1177 12

Homocysteine has been associated with the oxidative stress in the pathogenesis of atherosclerosis. Oxidative stress caused by triglycerides and free fatty acids is known to cause insulin resistance and hyperinsulinemia. On the other hand, insulin resistance may increase homocysteine levels. Since obesity is associated with insulin resistance and hyperinsulinemia, we aimed to study the possible association of homocysteine with hyperinsulinemia in obese subjects. 20 obese male subjects (body mass index >29), aged 33--55 (mean 45 years old) were studied. A fasting blood sample was obtained for the study and the subjects undertook an oral glucose tolerance test with samples taken at 1 and 2 h after glucose. Subjects were divided in two groups according to the fasting insulin levels, < 9 &mgr;U/ml or normoinsulinemic (group 1) and >9 &mgr;U/ml or hyperinsulinemic (group 2). Glucose, insulin, homocysteine, folate, B(12,) total cholesterol, HDL-cholesterol and triglycerides levels were determined in fasting blood samples. In oral glucose tolerance test, glucose, insulin and homocysteine levels were measured. Hyperinsulinemic obese subjects (group 2) had higher levels of insulin and glucose at 1 h and 2 h postglucose, compared with group 1. Fasting total homocysteine and triglyceride levels were also increased in this group, whereas folate and B(12) levels were similar in both groups. Fasting homocysteine significantly correlated with fasting insulin (r = 0.6, p <0.01). Homocysteine levels slightly but significantly decreased after glucose loading in normoinsulinemic but not in hyperinsulinemic obese subjects. These results show that higher homocysteine levels are observed in the hyperinsulinemic obese subjects and suggest that homocysteine could play a role in the higher risk of cardiovascular disease in obesity.
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PMID:Elevated plasma total homocysteine levels in hyperinsulinemic obese subjects. 1183 22

Homocysteine is considered to be an independent risk factor for atherosclerosis. Experimental animal models of hyperhomocysteinemia show aortic calcification, suggesting that this disorder is associated with aortic calcification in humans. A total of 28 patients with hyperlipidemia were enrolled into this study. The degree of aortic calcification at the level of the bifurcation and 1 cm proximal to the bifurcation was assessed by computed tomography of the aorta and the association between calcification of the aorta and the plasma level of homocysteine was then analyzed. The mean plasma homocysteine level in 28 patients was 8.7 microM. They were divided into 2 groups, high homocysteine level group (HHL; homocysteine level >8.7 microM) and low homocysteine level group (LHL; homocysteine level < = 8.7 microM). The degree of aortic calcification at the level of the bifurcation differed significantly between the two groups (19.1% vs. 10.5%; p < 0.01). We found that mild hyperhomocysteinemia was associated with aortic calcification, which suggests that interventions to reduce the plasma level of homocysteine may also reduce the severity of aortic calcification.
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PMID:Association of mild hyperhomocysteinemia with aortic calcification in hypercholesterolemic patients. 1186 36

Homocysteine is a significant but modifiable risk factor for vascular diseases. While several pathological processes may be involved, homocysteine can cause significant endothelial impairment and compromise vascular NO bioactivity. In the present study, we aimed to assess effects of homocysteine on NO-mediated hemodynamic responses in vivo. We created an acute hyperhomocysteinemia model (plasma homocysteine of 65-276 micromol/l) by continuous venous infusion of D,L-homocysteine to anaesthetized Sprague-Dawley rats. Vasodilators including NO donors: S-nitrosohomocysteine (SNOHcy), S-nitrosocysteine (SNOCys) and sodium nitroprusside (SNP), the endothelial NO synthase (eNOS) activator: acetylcholine (ACh), and calcium channel blocker: verapamil and nicardipine, were administered by one bolus injection to the homocysteinemic rats. While homocysteine infusion produced no change in the mean femoral arterial blood pressure, each of these vasodilators led to a rapid and substantial dose-dependent fall in blood pressure. Concurrent homocysteine infusion, however, attenuated the blood pressure lowering effects induced by NO donors (P<0.01), but not by the calcium channel blockers. Homocysteine inhibited not only the endothelial-derived NO as stimulated by ACh, but also the bioactivity of exogenously supplied NO by SNOHcy, SNOCys and SNP. Our findings indicate that homocysteine may have an effect on NO bioproduction and bioavailability. Vasodilating efficacy of commonly used NO donors such as nitroglycerine may be seriously compromised by hyperhomocysteinemia, which is common among ischemic heart disease patients.
Atherosclerosis 2002 Mar
PMID:Homocysteine attenuates hemodynamic responses to nitric oxide in vivo. 1188 29

Homocysteine may promote atherogenesis and thrombogenesis by enhancing leukocyte-endothelium interactions. We explored this hypothesis in an acute hyperhomocysteinemia rat model, which was created by a continuous venous homocysteine infusion (4 ml/h/kg body weight) with 2.5 and 10 mg/ml D,L-homocysteine upto 90 min. Venous homocysteine levels were monitored periodically and varied 65-276 micromol/l, a range observed frequently in homocysteinemic and homocystinuric patients. We measured hemodynamic parameters in mesentery by intravital microscopy in rats infused with homocysteine (N=5 for each dose) and saline (N=7). Homocysteine infusion for 90 min did not change the mean carotid arterial blood pressure, velocity of red blood cells and rolling leukocyte flux. However at the dose of 10 mg/ml the venular wall shear rate was reduced to 66-69% of the pre-infusion value (P<0.05). The leukocyte rolling velocity decreased to 78-82% (P<0.05). The number of leukocytes adhering to the venular wall increased 2.4-fold (P<0.05), and the leukocyte extravasation increased 4.7-fold (P<0.001). Each of these effects was time-dependent and homocysteine dose-dependent. But none were observed in saline infused rats. In conclusion, while homocysteine infusion did not change hemodynamic parameters, it significantly enhanced dose-dependent leukocyte-endothelium interactions, which may contribute to homocysteine induced endothelial dysfunction.
Atherosclerosis 2002 Mar
PMID:Leukocytes extravasation in acute homocysteinemic rats. 1188 30

Numerous clinical studies in Western and Asian countries suggest that individuals with elevated blood levels of homocysteine have an increased risk of atherosclerosis, myocardial infarction, cerebral infarction, and deep vein thrombosis. Homocysteine is also known to induce both atherogenic and thrombogenic mediators in cultured vascular cells so that homocysteine may influence the damage of endothelial cells, promote smooth muscle cell growth, induce atherogenic mediators and thrombus formation after coronary angioplasty. The association between homocysteine and restenosis after percutaneous coronary intervention (PCI) has been discussed. In this study, the relationship between plasma homocysteine levels and restenosis after PCI to investigate whether plasma homocysteine levels may be a predictor of restenosis after PCI was examined. One hundred consecutive patients who underwent successful PCI were enrolled and plasma homocysteine level was measured in all patients prior to PCI. Plasma for homocysteine level was obtained in 99 of 100 patients who had angioplasty. The mean plasma homocysteine concentration in the enrolled patients was 13.61 +/- 6.04 micromol/L. The minimum and maximum of plasma homocysteine were 4.40 micromol/L and 50.00 micromol/L, respectively. In healthy subjects, the normal reference range of homocysteine level is 5-15 micromol/L However, recent data suggest that some patients may be at increased cardiovascular and cerebrovascular risk at levels as low as 12 micromol/L. For this reason, both cut off points of homocysteine level > or = 15 micromol/L or > or = 12 micromol/L to identify the high homocysteine level group were used. Of 99 patients, high homocysteine level (> or = 15 micromol/L) was established in 9 patients with restenosis versus 20 patients without restenosis. If the cut off point of homocysteine level > or = 12 micromol/L was used, high homocysteine level was established in 14 patients with restenosis versus 39 patients without restenosis. From both cut off points of homocysteine level, there was no correlation between plasma homocysteine level and the restenosis group. (p>0.05).
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PMID:Homocysteine and restenosis after percutaneous coronary intervention. 1200 4

High levels of homocysteine induce a sustained injury on arterial endothelial cells which accelerates the development of thrombosis and atherosclerosis. Some of the described effects of homocysteine on endothelial cells are features shared with an anti-angiogenic response. Therefore, we studied the effects of homocysteine on key steps of angiogenesis using bovine aorta endothelial cells as a model. Homocysteine decreased proliferation and induced differentiation. Furthermore, 5 mM homocysteine produced strong inhibitions of matrix metalloproteinase-2 and urokinase, two proteolytic activities that play a key role in extracellular matrix re-modeling, and decreased migration and invasion, other two key steps of angiogenesis. This study demonstrates that homocysteine can inhibit several steps of the angiogenic process.
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PMID:Anti-angiogenic effects of homocysteine on cultured endothelial cells. 1205 28


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