Abstract 1671: Adiponectin Increases DAB2, a Tumor Suppressor Gene, in Human Aortic Smooth Muscle Cells via AMPK Activation
Atherosclerosis and restenosis are characterized, in part, by increased proliferation of vascular smooth muscle cells (VSMC) and the progression of neointimal lesion formation. Adiponectin is a fat-derived 30kDa cytokine abundant in human plasma that exerts protective effects on the vasculature. Previous studies have shown that VSMC proliferation and migration are diminished by treatment with adiponectin. However, the molecular mechanism(s) whereby adiponectin inhibits VSMC proliferation is unknown. Studies have shown that the cellular actions of adiponectin are mediated via the activation of AMP-activated protein kinase (AMPK). Moreover, it has been shown that activation of AMPK activity inhibits VSMC proliferation. Thus, to identify genes that are involved in the adiponectin-mediated suppression of VSMC proliferation, we performed microarray analysis on human aortic smooth muscle cells (HAoSMCs) treated with adiponectin in the presence or absence of an AMPK inhibitor, Compound C. We identified disabled 2 (DAB2) as a gene whose expression was differentially expressed by adiponectin treatment of HAoSMCs. DAB2 is a phosphoprotein that is implicated in cancer as a tumor suppressor gene. Using quantitative real-time PCR, we confirmed that adiponectin increases DAB2 mRNA expression by approximately 2-fold compared to vehicle. Stimulation of HAoSMCs with adiponectin and Compound C abrogated this increase in DAB2 expression. Thus, it appears that adiponectin increases DAB2 expression, in part, through activation of AMPK activity. To determine whether DAB2 is down-regulated by pro-proliferative growth factors, we performed time-course experiments with PDGF-BB, a potent inducer of VSMC proliferation. We found that PDGF-BB inhibits DAB2 expression in a time-dependent fashion. Altogether, our findings implicate DAB2 as an important mediator of the anti-proliferative effects of adiponectin in VSMC.