PPAR gamma 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 PPAR alpha activation abolishes LDL effects in human aortic SMCs (hAoSMCs). Herein is the first report of PPAR gamma activation by troglitazone (TG) exerting its inhibitory effects on LDL-induced cell proliferation via generation not of H2O2, but of O-2(.-), and the subsequent activation of Erk1l/2 in hAoSMCs. Moreover, in this study TG abolished the LDL-accelerated G(1)-S progression to control levels via down-regulation of active cyclinDI/CDK4 and cyclinE/CDK2 complexes and up-regulation of p21(Cip1) expression. TG exerted its anti-prolifekative effects through the up-regulation of basal superoxide dismutase (SOD) expression. This data suggests that the regulation of O-2(.-) is located at the crossroads between LDL signaling and cell proliferation. (c) 2007 Elsevier Inc. All rights reserved.