ReviewHomocysteine and cardiovascular disease:: Current evidence and future prospects
Section snippets
Homocysteine metabolism
Homocysteine, a highly reactive sulfur-containing amino acid, is an intermediary product of methionine metabolism. Methionine is converted to S-adenosylmethionine, a methyl group donor for several intracellular reactions. Following the transfer of a methyl group, it is transformed into S-adenosylhomocysteine, the immediate precursor of homocysteine (Figure 2). Homocysteine itself can be either retransformed to methionine or degraded to cysteine. The resynthesis of methionine requires a
Endothelium.
Homocysteine causes acute and chronic endothelial dysfunction. The mechanisms involved include the synthesis of hydrogen peroxide (8), generation of superoxide anion radicals (9), decreased release of nitric oxide (10), increased leukocyte-endothelium interactions by upregulation of cell adhesion molecules (11), and alterations of the intracellular redox state, thus eliciting a stress response (13). A substantial alteration in gene expression has been reported in endothelial cells exposed to
Discussion
The deleterious effects of homocysteine on vascular function and blood coagulation provide a pathophysiologic explanation for the increased risk of cardiovascular morbidity and mortality associated with hyperhomocysteinemia. Homocysteine-lowering therapy might provide cardiovascular protection by enhancing endothelial function and reducing arterial intimal-medial thickness, wall stiffness, and, possibly, procoagulant activity. Preliminary data show that high intake of fruit and vegetables, the
Acknowledgements
We thank Alex Dionysiou for his technical support.
References (101)
- et al.
Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria
Kidney Int
(1999) - et al.
Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase
J Biol Chem
(1997) - et al.
Homocysteine provokes leukocyte-endothelium interaction by downregulation of nitric oxide
Gen Pharmacol
(1999) - et al.
Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of the c-Jun NH2-terminal kinase and promoter response element
Blood
(2000) - et al.
Homocysteine-induced endoplasmatic reticulum stress and growth arrest leads to specific changes in gene expression in human endothelial cells
Blood
(1999) - et al.
Homocysteine and hemostasispathogenic mechanisms predisposing to thrombosis
J Nutr
(1996) - et al.
Enhancement by homocysteine of plasminogen activator inhibitor-1 gene expression and secretion from vascular endothelial and smooth muscle cells
Biochem Biophys Res Commun
(2000) - et al.
Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis
Blood
(2000) - et al.
Homocysteinemia due to folate deficiency
Metabolism
(1987) - et al.
Prevalence of familial mild hyperhomocysteinemia
Atherosclerosis
(1996)
Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate
Am J Cardiol
Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease
Atherosclerosis
Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men
Lancet
Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus
Lancet
Plasma total homocysteine and cardiovascular and noncardiovascular mortalitythe Hordaland Homocysteine Study
Am J Clin Nutr
Plasma total homocysteine and risk of angina pectoris with subsequent coronary artery bypass surgery
Am J Cardiol
Relation of serum homocyst(e)ine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study
Atherosclerosis
Treatment of hyperhomocysteinemia with folic acid and vitamins B12 and B6 attenuates thrombin generation
Thromb Res
Plasmatic homocysteine response to vitamin supplementation in elderly people
Thromb Res
Emerging noninvasive biochemical measures to predict cardiovascular risk
Arch Intern Med
Hyperhomocysteinemia: an independent risk factor for cardiovascular disease
N Engl J Med
Hyperhomocysteinemia: a significant risk factor for cardiovascular disease in renal transplant recipients
Nephrol Dial Transplant
Plasma homocysteine levels and mortality in patients with coronary artery disease
N Engl J Med
Nonfasting plasma total homocysteine levels and all-cause cardiovascular disease mortality in elderly Framingham men and women
Arch Intern Med
Hyperhomocysteinemia increases risk of death, especially in type-2 diabetes: 5-year follow-up of the Hoorn Study
Circulation
Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine
J Clin Invest
Biochemical evidence for a link between elevated levels of homocysteine and lipid peroxidation in vivo
Curr Atheroscler Rep
Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia
J Clin Invest
Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta
Arterioscler Thromb Vasc Biol
Hyperhomocysteinemia is a risk factor for endothelial dysfunction in humans
Circulation
Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis
Proc Natl Acad Sci
Homocysteine is a modulator of platelet-derived growth factor action in vascular smooth muscle cellsa possible role for hydrogen peroxide
Br J Pharmacol
Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells
FASEB J
Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study
Circulation
Carotid and femoral artery wall thickness and stiffness in patients at risk for cardiovascular disease, with special emphasis on hyperhomocysteinemia
Arterioscler Thromb Vasc Biol
Association between elevated plasma total homocysteine and increased common carotid artery wall thickness
Ann Med
Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening
Circulation
Hyperhomocysteinemia-induced vascular damage in the minipig: captopril-hydrochlorothiazide combination prevents elastic alterations
Circulation
The arterial system in human hypertension
Acute hyperhomocysteinemia induces a reduction in arterial distensibility and compliance
J Hypertens
Influence of biochemical alterations on arterial stiffness in patients with end-stage renal disease
Arterioscler Thromb Vasc Biol
Plasma homocysteine, aortic stiffness, and renal function in hypertensive patients
Hypertension
Carotid artery stiffness in patients with end-stage renal disease: no effect of long-term homocysteine-lowering therapy
Clin Nephrol
Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine
J Clin Invest
Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats
FASEB J
Homocyst(e)ine, diet, and cardiovascular diseases. A statement for healthcare professionals from the nutrition committee, American Heart Association
Circulation
Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary heart diseaseEuropean COMAC Group
Circulation
Total homocysteine in plasma and serummethods and clinical applications
Clin Chem
A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase
Nat Genet
Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations
Circulation
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