PPARγ activation abolishes LDL-induced proliferation of human aortic smooth muscle cells via SOD-mediated down-regulation of superoxide

Abstract

Native LDL would be a mitogenic and chemotactic stimulus of VSMC proliferation and differentiation in the atherosclerotic lesion where endothelial disruption occurred. In previous studies, our group investigated the molecular mechanisms by which LDL induces IL-8 production and by which PPARα activation abolishes LDL effects in human aortic SMCs (hAoSMCs). Herein is the first report of PPARγ activation by troglitazone (TG) exerting its inhibitory effects on LDL-induced cell proliferation via generation not of H2O2, but of O2{radical dot} -, and the subsequent activation of Erk1/2 in hAoSMCs. Moreover, in this study TG abolished the LDL-accelerated G1-S progression to control levels via down-regulation of active cyclinD1/CDK4 and cyclinE/CDK2 complexes and up-regulation of p21Cip1 expression. TG exerted its anti-proliferative effects through the up-regulation of basal superoxide dismutase (SOD) expression. This data suggests that the regulation of O2{radical dot} - is located at the crossroads between LDL signaling and cell proliferation.