E012 Smooth muscle cell proliferation elicited by hydrogen peroxide involves the metalloprotease/sphingolipid pathway - 17/04/09
Résumé |
Smooth muscle cell (SMC) proliferation is a common response to vascular stress and a central feature in vascular diseases, such as atherosclerosis, restenosis and allograft vasculopathy. Among the variety of signaling pathways implicated in stress-induced SMC proliferation, oxidative stress and the sphingolipid pathway play a critical role. The molecular link between reactive oxygen species and the activation of the sphingolipid pathway is only partly understood. This study was carried out to investigate the role of the sphingolipid pathway in the mitogenic signaling elicited by of H2O2 in SMC.
Low concentration of H2O2 triggered SMC proliferation through a signaling pathway involving the activation of MMP2 metalloprotease, and neutral sphingomyelinase-2 (nSMase2). Inhibition of MMP2 by Batimastat, a broad-specificity MMP inhibitor, or the defect of MMP2-/- (fibroblasts from MMP2 deficient mice) blocked the H2O2- induced activation of nSMase2 and DNA synthesis, suggesting that all this enzyme activity is dependent on MMP2 activation. The genetic defect of nSMase2 (fibroblasts from nSMase2-deficient fro/ fro mice), and the use of nSMase2 specific siRNA did not inhibit the H2O2-induced activation of MMP2, but blocked the DNA synthesis.
In conclusion, these data shed light on a novel mechanism of stress-induced mitogenic response to low concentration of H2O2, involving the sequential action of MMP2 and nSMase2 with possible consequences under conditions leading to increased oxidative stress in the vascular wall.
Le texte complet de cet article est disponible en PDF.Vol 102 - N° S1
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