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 significance of homocysteine, however, the molecular mechanisms of homocysteine-induced arteriosclerosis have not been completely elucidated. This lack of understanding is due in large part to the excessively high concentrations of homocysteine (greater than 1 mM) used in experiments. Many of homocysteine's effects have been attributed to its prooxidant activity, which is implicated as the mechanism through which it inhibits production of endothelium-derived relaxing factor and activates quiescent vascular smooth muscle cells. We have found that homocysteine at 10 to 50 microM (but not cysteine) inhibits progression of the vascular endothelial cell cycle at or before the G1-S junction. This inhibition appears to be mediated by decreases in the carboxyl methylation, membrane association, and activity of p21ras--a major G1 regulator. Homocysteine may play an important role in promoting arteriosclerosis by inducing endothelial dysfunction, by inhibiting endothelial cell regeneration, and by directly activating quiescent vascular smooth muscle cells.
Lee
M E
ME
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA.
Wang
H
H
D001161:Arteriosclerosis / Q000209:etiology; D002245:Carbon Dioxide / Q000037:antagonists & inhibitors; D002462:Cell Membrane / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005609:Free Radicals / Q000037:antagonists & inhibitors; D016193:G1 Phase / Q000187:drug effects; D006710:Homocysteine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008745:Methylation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D016877:Oxidants / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors; D012038:Regeneration / Q000187:drug effects; D012307:Risk Factors; D016196:S Phase / Q000187:drug effects; D014652:Vascular Diseases / Q000209:etiology*; D020246:Venous Thrombosis / Q000209:etiology
D005609:Free Radicals; D016877:Oxidants; D006710:Homocysteine; D002245:Carbon Dioxide; C041069:carboxyl radical; D009569:Nitric Oxide; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)