Homocysteine, atherogenesis and thrombosis

Abstract

Clinical studies indicate that moderately elevated levels of homocysteine are associated with both atherosclerosis and venous thrombosis. We review new studies that shed light on potential mechanisms for the vascular toxicity of homocysteine. Homocysteine stimulates vascular smooth muscle cells to proliferate and to synthesize collagen, hallmarks of atherogenesis. Homocysteine also adversely effects the anticoagulant systems that are mediated by the vascular endothelium. Homocysteine inhibits the expression and activity of endothelial cell-surface thrombomodulin, the thrombin cofactor responsible for protein C activation. Homocysteine inhibits the antithrombin III binding activity of endothelial heparan sulfate proteoglycan, thereby suppressing the anticoagulant effect of AT III. Homocysteine has been found to inhibit the fibrinolytic properties of the endothelial surface by inhibiting the binding of tissue plasminogen activator to a cell-surface receptor. Homocysteine also stimulates HUVEC tissue factor activity. The binding of lipoprotein(a) (Lp(a)) to fibrin may explain, in part, its atherogenicity. Homocysteine dramatically enhances the affinity between Lp(a), and fibrin providing a link between elevated levels of homocysteine, Lp(a) and atherosclerosis.