Impaired Homocysteine Metabolism and Atherothrombotic Disease

Abstract

SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

Protein and lipid oxidative damage and complex I content are lower in the brain of budgerigar and canaries than in mice. Relation to aging rate

“…Homocysteine levels increase with age in humans and they are a risk factor for aging and many chronic degenerative diseases (Drögue 2001;Durand et al 2001;Ninomiya et al 2004;Ferrari 2004). Homocysteine has a free thiol group that can be readily oxidized and generates protein mixed disulfides or thiol bridges between proteins.…”

Bovine Theileriosis: Effects on the Status of Thyroid Hormones, Homocystein, Serum Lipids and Lipoproteins

“…Although there have been no documented or incisive investigations on homocystein changes in blood parasites of animals, several publications on human cardiovascular diseases (CAD) correlate hyperhomocysteinemia with coronary, cerebral and peripheral artery disease, as well as venous thrombosis (Nygard et al, 1997;Ganguly and Alam, 2015). In addition, the pathogenesis of the vascular injury caused by an increase of Hcy includes damage to the endothelial cell, increased oxidation of LDL-cholesterol with deposits in the vessel wall and direct activation of the coagulation cascade (Durand et al, 2001). On the other hand, Hcy has been demonstrated to increase oxidative Res.…”

Factors Affecting S-Homocysteinylation of LDL Apoprotein B

“…Increased plasma homocysteine (Hcy) 3 is an independent risk factor for vascular disease in humans (1,2 ). Although the exact mechanism of Hcy toxicity is unknown, several mechanisms have been investigated that may explain its role in atherosclerosis pathogenesis (3,4 ), including endothelial injury, reduction of vascular nitric oxide (NO) production and bioavailability, mitotic effect on smooth muscle cells, influence on leukocyte behavior and hemostasis, and oxidative modification of LDL.…”

“…Although the exact mechanism of Hcy toxicity is unknown, several mechanisms have been investigated that may explain its role in atherosclerosis pathogenesis (3,4 ), including endothelial injury, reduction of vascular nitric oxide (NO) production and bioavailability, mitotic effect on smooth muscle cells, influence on leukocyte behavior and hemostasis, and oxidative modification of LDL. Recent study results have suggested that Hcy-induced vascular damage could be a result of Hcy-thiolactone (HcyT), an Hcy-reactive product formed in several cell types as a result of editing reactions of some aminoacyl-tRNA synthetase (5,6 ).…”