Homocysteine and hypomethylation - A novel link to vascular disease

A mild elevation in serum homocysteine levels is an independent risk factor for arteriosclerosis and venous thrombosis. Despite the clinical significa nce of homocysteine, however, the molecular mechanisms of homocysteine-indu ced arteriosclerosis have not been completely elucidated. This lack of unde rstanding is due in large part to the excessively high concentrations of ho mocysteine (greater than 1 mM) used in experiments. Many of homocysteine's effects have been attributed to its prooxidant activity, which is implicate d as the mechanism through which it inhibits production of endothelium-deri ved relaxing factor and activates quiescent vascular smooth muscle cells. W e have found that homocysteine at 10 to 50 mu M (but not cysteine) inhibits progression of the vascular endothelial cell cycle at or before the GI-S j unction. This inhibition appears to be mediated by decreases in the carboxy l methylation, membrane association, and activity of p21(ras)-a major GI re gulator Homocysteine may play art important role in promoting arteriosclero sis by inducing endothelial dysfunction, by inhibiting endothelial cell reg eneration, and by directly activating quiescent vascular smooth muscle cell s. (C) 1999, Elsevier Science Inc.