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Homocysteine and hypomethylation. A novel link to vascular disease
1Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA.
Insights
Mild elevations in serum homocysteine contribute to arteriosclerosis. This study reveals homocysteine inhibits endothelial cell cycle progression by affecting p21ras, a key regulator, offering new insights into vascular disease mechanisms.
Area of Science:
- Cardiovascular Biology
- Cell Cycle Regulation
- Molecular Medicine
Background:
- Mild elevation in serum homocysteine is a known risk factor for arteriosclerosis and venous thrombosis.
- Molecular mechanisms underlying homocysteine-induced arteriosclerosis remain incompletely understood, partly due to the use of excessively high experimental concentrations.
- Homocysteine's prooxidant activity is implicated in inhibiting endothelium-derived relaxing factor and activating vascular smooth muscle cells.
Purpose of the Study:
- To elucidate the molecular mechanisms by which homocysteine contributes to arteriosclerosis.
- To investigate the effects of physiologically relevant homocysteine concentrations on vascular endothelial cells.
- To identify specific molecular targets of homocysteine action in the vascular system.
Main Methods:
- Investigated the effect of homocysteine (10-50 microM) on vascular endothelial cell cycle progression.
- Assessed the impact of homocysteine on carboxyl methylation, membrane association, and activity of p21ras.
- Compared the effects of homocysteine with cysteine at similar concentrations.
Main Results:
- Homocysteine, but not cysteine, at concentrations of 10 to 50 microM inhibits vascular endothelial cell cycle progression at the G1-S junction.
- This cell cycle inhibition is associated with decreased carboxyl methylation, membrane association, and activity of p21ras, a critical G1 regulator.
- Findings suggest a mechanism distinct from previously proposed prooxidant effects at high concentrations.
Conclusions:
- Homocysteine plays a significant role in promoting arteriosclerosis through endothelial dysfunction and impaired endothelial cell regeneration.
- Homocysteine's inhibition of the endothelial cell cycle, mediated by p21ras, is a key mechanism contributing to vascular disease.
- These findings highlight the importance of understanding homocysteine's molecular actions at physiologically relevant levels for therapeutic strategies against arteriosclerosis.
Abstract:
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.