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)

Homocystinemia has been identified as an independent risk factor for atherosclerosis. Monocyte chemoattractant protein-l (MCP-l) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall. The authors investigated the role of intracellular redox status in the expression of MCP-l stimulated by homocysteine in endothelial cells. Homocysteine stimulated MCP-1 mRNA expression and protein production in a time-dependent and dose-dependent manner in endothelial cells, decreased intracellular glutathione (GSH) and protein thiol levels, as well as G6PDH activity and NADPH levels. Thiol reduced reagents, GSH, and dithiothreitol levels, and reversed the MCP-l mRNA expression and protein production in endothelial cells; in addition, thiol oxidized reagent, diamide, and BSO levels, and markedly potentiated homocysteine-mediated up-regulation of MCP-l mRNA expression and protein production in endothelial cells. These results demonstrate that homocysteine can trigger overexpression of the MCP-1 gene by altering the intracellular redox status, suggesting that the homocysteine-induced changes in the intracellular redox status play an important role in modulating the expression of MCP-l in endothelial cells.
 ...
PMID:Intracellular redox status modulates monocyte chemoattractant protein-1 expression stimulated by homocysteine in endothelial cells. 1288 31

Elevated plasma homocysteine is an independent risk factor for atherosclerosis. An important initial step of atherosclerosis is the adhesion and infiltration of monocytes to the lesion site. It has been shown that the pro-inflammatory cytokine interleukin-8 can rapidly cause rolling monocytes to adhere firmly onto monolayers expressing E-selectin. The objective of the present study was to investigate the effect of homocysteine on interleukin-8 production in human endothelial cells. Cells were incubated with various concentrations of homocysteine for 20 h. The gene expression was determined by real-time PCR and the interleukin-8 protein was measured by immunoassay analysis. Homocysteine enhanced the expression of interleukin-8 in a dose-dependent manner (181% of controls at 2.5 mmol/l homocysteine). Stimulation of gene expression was associated with a parallel increase in interleukin-8 protein synthesis (160% of controls at 5.0 mmol/l homocysteine). By co-incubation of endothelial cells with homocysteine and copper sulfate, a further elevation of interleukin-8 expression (251% of controls) was observed, whereas copper sulfate alone had no stimulatory effect. In conclusion, the present study demonstrated that homocysteine altered endothelial cell function by stimulating interleukin-8 expression, suggesting a contribution of homocysteine to the initiation and progression of atherosclerosis. The formation of homocysteine-induced oxidation products might serve as one of the underlying mechanisms of this effect.
 ...
PMID:Stimulatory effect of homocysteine on interleukin-8 expression in human endothelial cells. 1296 12

Homocysteine appears to be causally related to cardiovascular disease and shown to induce endothelial dysfunction. An adverse effect on large elastic arteries has not been reported. In 18 healthy middle-aged subjects, systemic arterial compliance (SAC) was measured over 5h after a standard methionine load. Arterial pressure waves from the carotid artery and aortic flow were measured non-invasively and SAC calculated. Differences in mean SAC values when plasma homocysteine concentrations were raised with a methionine containing meal and on another day when a control meal was eaten were highly significant. SAC fell (arterial stiffness increased) by 22% at 2.5h and by 19% at 5h (treatment x time interaction: P=0.003 and 0.004, respectively). Adjustment for confounders (age, arterial pressure, BMI, LDL cholesterol) did not affect conclusions. Thus, arterial stiffness in the central elastic arterial system increased rapidly at high plasma homocysteine concentrations.
Atherosclerosis 2003 Nov
PMID:Arterial stiffness is rapidly induced by raising the plasma homocysteine concentration with methionine. 1464 9

Hyperhomocysteinemia is an established risk factor for atherosclerosis, thrombosis and other vascular diseases. Homocysteine auto-oxidation is considered to be crucially involved in the pathogenesis of these diseases. However, the question remains to be elucidated whether vitamin deficiency and homocysteine accumulation are causal for disease development or rather comprise a secondary phenomenon. Most diseases accompanied by hyperhomocysteinemia are also associated with ongoing activation of the immune system. In vitro experiments show homocysteine to accumulate in stimulated peripheral blood mononuclear cells. In patients with coronary heart disease, with rheumatoid arthritis and in patients with dementia, an association between cellular immune activation and homocysteine metabolism is found. Homocysteine concentrations not only correlate inversely with folate concentrations, they also show a positive relationship with concentrations of immune activation markers like neopterin. Moreover, in patients with various kinds of dementia, increased concentrations of serum peroxides, homocysteine and neopterin correlate with each other. Studies support a role of immune system activation in the development of hyperhomocysteinemia. Stimulation and proliferation of immune cells may lead to the production of reactive oxygen species that may oxidize antioxidants and oxidation-sensitive B-vitamins. An enhanced demand for antioxidants as well as folate and vitamin B12 may develop, together with hyperhomocysteinemia, despite sufficient dietary intake.
 ...
PMID:Hyperhomocysteinemia and immune activation. 1465 23

Coronary heart disease often occurs in the absence of traditional risk factors. Consequently, epidemiological studies exploring novel risk factors are necessary to improve the prediction of coronary heart disease. This study evaluated five promising markers of cardiovascular risk: homocysteine, C-reactive protein, fibrinogen, lipoprotein(a) (Lp(a)), free apolipoprotein(a) (apo(a)) and Lp(a) phenotypes. The study included 135 patients with angiographically confirmed atherosclerosis. The control group consisted of 93 sex- and age-matched individuals. The Mann-Whitney U-test was used for group comparison. New risk factors were evaluated by binary logistic regression. The odds ratios were calculated continuously for homocysteine in dependence on C-reactive protein. Low density lipoprotein (LDL)-cholesterol was nearly identical in controls and patients. Homocysteine, C-reactive protein, fibrinogen, high density lipoprotein (HDL)-cholesterol and Lp(a) discriminated highly significantly between both groups. The continuously calculated odds ratio for homocysteine demonstrated a distinct influence of C-reactive protein. In the group with high C-reactive protein levels, homocysteine levels above 9.6 micromol/l resulted in a markedly elevated risk (odds ratio 12), in the group with C-reactive protein levels below 5 mg/dl, a comparable risk increase was observed at a homocysteine level of 16.6 micromol/l. This data strongly suggests that plasma homocysteine helps identify individuals at risk, especially among those with elevated C-reactive protein levels.
 ...
PMID:The impact of hyperhomocysteinemia as a cardiovascular risk factor in the prediction of coronary heart disease. 1465 34

Homocysteine is a sulphur aminoacid with a free thiol group which is not present in dietary protein. This aminoacid is a secondary f methionine by-product from cysteine metabolism. The pathogenic mechanisms of homocysteine in vascular damage have not been clarified. At present, it is no possible to develop an atherogenic and thrombogenic hypothesis. Yet high levels of homocysteine can cause endothelial damage, with increased thrombosis and atherosclerosis. Hyperhomocysteinemia has been reported in patients with diabetes mellitus type 1 and type 2; the prevalence and secondary cardiovascular risk is higher in patients with diabetes type 2 than those with diabetes type 1. In patients with diabetes mellitus type 1, microvascular and macrovascular complications and neuropathy are found to be increased in those with hyperhomocysteinemia. In patients with diabetes mellitus type 2, the relationship between hyperhomocysteinemia, macrovascular complications and renal disease is unclear; however, a higher prevalence of macrovascular complications in diabetic patients with hyperhomocisteinemia is associated with a higher prevalence of renal disease. Moreover, patients with hyperhomocysteinemia have hypertension and dyslipemia. Multivariate regression analyses have shown an independent relationship between homocysteine and macrovascular complications. The relationship between retinopathy and homocysteine has not been clarified. In summary, hyperhomocysteinemia could be a risk factor accounting for chronic complications in diabetic patients. Nevertheless, it is necesary to perform more prospective and intervention studies to clarify the independent risk of homocysteine and thus assay alternative treatments.
 ...
PMID:[Homocysteine in patients with diabetes mellitus]. 1473 72

Moderate hyperhomocysteinemia is associated with an increased risk of atherosclerosis, thrombosis and neurodegenerative diseases. Homocysteine accumulation in the blood can be due to many underlying causes, which may interact with each other, e.g. genetic disposition and B-vitamin status. The role of the sulfur-containing amino acid homocysteine in the pathogenesis of diseases remains unclear, even if many studies suggest a causal relationship between homocysteine-mediated processes like oxidative stress, NO-inactivation and endothelial deficiency and atherogenesis. Proposed mechanisms of action of homocysteine are discussed, and the question is addressed, whether effects that are attributed to homocysteine, are not rather the consequence of folate and vitamin B12-deficiency. Deficiency of these B-vitamins in parallel with moderate hyperhomocysteinemia is often found in patients with enhanced activation of the cellular immune system, like Alzheimer's disease, rheumatoid arthritis and also vascular diseases. In patients with these diseases an association between homocysteine metabolism, oxidative stress and immune activation exists. On the one hand proliferation of immunocompetent cells having an enhanced demand for B-vitamins leads to the accumulation of homocysteine. On the other hand macrophages stimulated by TH1-type cytokine interferon-gamma form reactive oxygen species (ROS), which oxidize antioxidants, lipoproteins and oxidation-sensitive B-vitamins. Thereby Th1-type immune response could contribute importantly to the development of hyperhomocysteinemia, and may also be a major determinant of disease progression.
 ...
PMID:Moderate hyperhomocysteinemia and immune activation. 1496 13

Homocysteine (Hcy) is a sulfur-containing metabolite of methionine and is an emerging independent risk factor for atherosclerosis. Previous studies have shown that age, gender, renal function and folic acid intake are the main factors influencing total plasma Hcy levels in humans. A unique approach to the science of human longevity is the natural model of centenarians. The objective of this study was to verify whether the previously determined risk factors for atherosclerosis and atherosclerosis-related diseases change with age and, finally, to establish the vitamin nutritional status role. We studied 54 centenarians (14 males and 40 females) aged between 100-107 years (mean age 102.6+/-1.8 years) living in Sicily (Italy), recruited via the Registry Office, and compared them with three control groups composed of subjects with different age ranges. Total plasma Hcy, folate, vitamin B12 and pyridoxal phosphate (PLP) levels were compared between the groups by the Student's t test. The comparison between centenarians and <65-year old, randomly selected individuals showed that in centenarians the mean value of serum creatinine levels was 18 micromol/l (p=0.000) higher, the mean total Hcy value was 22 micromol/l higher (p=0.000), the mean PLP value was 17.9 nmol/l lower (p=0.000), the mean folate level was 2.1 nmol/l lower (p<0.001) and vitamin B12 was 70.5 pmol/l lower (p=0.000). The comparison between centenarians and >65-year old, randomly selected individuals showed that in centenarians the mean value of serum creatinine levels was 8 micromol/l higher (p=0.037), the mean total Hcy value was 11.6 micromol/l higher (p=0.000) and the mean PLP value was 4.2 nmol/l higher (p=0.000). It seems that centenarians are protected by some mechanism (maybe genetic) that allows them a long survival despite the high value of homocysteinemia. On the other hand, it can by hypothesized that good vitamin intake is essential to live over 100 years.
 ...
PMID:Elevated plasma total homocysteine in centenarians. 1508 May 65

The increasing number of older people is characteristic for most industrialised nations and implicates the known psychosocial and economic consequences. Therefore, an optimal nutrient supply that promotes continuing mental and physical well-being is particularly important. In this respect, vitamin B(12) and folic acid play a major role, since deficiency of both vitamins is associated with the pathogenesis of different diseases such as declining neurocognitive function and atherosclerotic lesions. Vitamin B(12) and folic acid act as coenzymes and show a close molecular interaction on the basis of the homocysteine metabolism. In addition to the serum concentrations of the vitamins, the metabolites homocysteine and methylmalonic acid are sensitive markers of cobalamin and folate status. Depending on the used marker, 3-60% of the elderly are classified as vitamin B(12) deficient and about 29% as folate deficient. Predominantly, this high prevalence of poor cobalamin status is caused by the increasing prevalence of atrophic gastritis type B, which occurs with a frequency of approximately 20-50% in elderly subjects. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal digestion and absorption of both B vitamins. This is the reason why an insufficient vitamin B(12) status in the elderly is rarely due to low dietary intake. In contrast, folic acid intake among elderly subjects is generally well below the recommended dietary reference values. Even moderately increased homocysteine levels or poor folate and vitamin B(12) status are associated with vascular disease and neurocognitive disorders. Results of a meta-analysis of prospective studies revealed that a 25% lower homocysteine level (about 3 micromol/L) was associated with an 11% lower ischemic heart disease risk and 19% lower stroke risk. It is still discussed, whether hyperhomocysteinemia is causally related to vascular disease or whether it is a consequence of atherosclerosis. Estimated risk reduction is based on cohort studies, not on clinical trials. Homocysteine initiates different proatherogenetic mechanisms such as the formation of reactive oxygen species and an enhanced fibrin synthesis. Supplementation of folic acid (0.5-5 mg/d) reduces the homocysteine concentration by 25%. Additional vitamin B(12) (0.5 mg/d) induces further reduction by 7%. In secondary prevention, supplementation already led to clinical improvements (reduction of restenosis rate and plaques). Depression, dementia, and mental impairment are often associated with folate and vitamin B(12) deficiency. The biochemical reason of this finding may be the importance of folic acid and vitamin B(12) for the transmethylation of neuroactive substances (myelin, neurotransmitters) which is impaired in vitamin deficiency ("hypomethylation hypothesis"). In recent years, there is increasing evidence for a role of folic acid in cancer prevention. As a molecular mechanism of a preventive effect of folic acid the hypomethylation of certain DNA sections in folate deficiency has been suggested. Since folate and vitamin B(12) intake and status are mostly insufficient in elderly subjects, a supplementation can generally be recommended.
 ...
PMID:[Age-associated changes in the metabolism of vitamin B(12) and folic acid: prevalence, aetiopathogenesis and pathophysiological consequences]. 1510 81

Homocysteine has emerged as a novel independent marker of risk for the development of cardiovascular disease over the past three decades. Additionally, there is a graded mortality risk associated with an elevated fasting plasma total homocysteine (tHcy). Metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are now considered to be a strong coronary heart disease (CHD) risk enhancer and a CHD risk equivalent respectively. Hyperhomocysteinemia (HHcy) in patients with MS and T2DM would be expected to share a similar prevalence to the general population of five to seven percent and of even greater importance is: Declining glomerular filtration and overt diabetic nephropathy is a major determinant of tHcy elevation in MS and T2DM. There are multiple metabolic toxicities resulting in an excess of reactive oxygen species associated with MS, T2DM, and the accelerated atherosclerosis (atheroscleropathy). HHcy is associated with an increased risk of cardiovascular disease, and its individual role and how it interacts with the other multiple toxicities are presented.The water-soluble B vitamins (especially folate and cobalamin-vitamin B12) have been shown to lower HHcy. The absence of the cystathionine beta synthase enzyme in human vascular cells contributes to the importance of a dual role of folic acid in lowering tHcy through remethylation, as well as, its action of being an electron and hydrogen donor to the essential cofactor tetrahydrobiopterin. This folate shuttle facilitates the important recoupling of the uncoupled endothelial nitric oxide synthase enzyme reaction and may restore the synthesis of the omnipotent endothelial nitric oxide to the vasculature.
 ...
PMID:Homocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: the pleiotropic effects of folate supplementation. 1513 82


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