Elevated plasma levels of homocysteine have been identified as an important and independent risk bral, coronary, and peripheral atherosclerosis, although the mechanisms are unclear. Homocysteine has been shown to promote cell proliferation and induction of the gene transcription factor c-/os in vascular smooth muscle cells. Earlier reports have suggested that homocysteine exert its effect via hydrogen peroxide (H202) produced during its metabolism. To evaluate the contribution of homocysteine to the pathogenesis of vascular diseases, we examined whether the effect of homocysteine on vascular smooth muscle cell growth is mediated by H202. We observed that 1.0 mM homocysteine induces DNA synthesis by 1.5-fold and proliferation of vascular smooth muscle cells two-fold in the presence of peroxide scavenging enzyme, catalase (2,600 U/ml). Our results suggest that homocysteine induces smooth muscle cell growth by an H202-independent pathway and that the effects of homocysteine may sum together with the known initiating events produced by oxidative stress and accelerate the progression of atherosclerosis. Antiox. Redox Signal. 1, 365-369.
Hyperhomocysteinemia has been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promote atherosclerotic plaque formation are not clearly defined. Earlier reports have suggested that homocysteine exert its effect via the H2O2 produced during its metabolism. To evaluate which signalling molecules are involved in homocysteine induced atherosclerotic changes during the pathogenesis of vascular diseases, we examined homocysteine induced smooth muscle cell proliferation in the presence of different signal transduction inhibitors. We show that MAPK kinase pathway is involved in homocysteine induced DNA synthesis and proliferation of vascular smooth muscle cells in the presence of the peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through a pathway that is independent of H2O2, that involves MAPK kinase activation, and that results in accelerated atherosclerosis.
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