Adiponectin Induces Vascular Smooth Muscle Cell Differentiation via Repression of Mammalian Target of Rapamycin Complex 1 and FoxO4

Abstract

Objective— The adipocyte-secreted hormone adiponectin exerts important cardioprotective and antidiabetic effects. Little is known about its effect on vascular smooth muscle cells (VSMC), key cells in restenosis, hypertension, and atherosclerosis. Methods and Results— Using human coronary artery VSMC, we found that recombinant adiponectin in the high-molecular-weight or trimeric forms but not the globular form induced VSMC differentiation through a mechanism similar to the classic feedback signaling used by rapamycin, a drug known to effectively inhibit restenosis on drug-eluting stents. Using a combination of pharmacological agents, small interfering RNA, and overexpression approaches, we demonstrated that adiponectin activated 5′-AMP-activated protein kinase α2 isoform, leading to inhibition of mammalian target of rapamycin complex 1 and S6K1. This in turn stabilized insulin receptor substrate-1, driving Akt2-mediated inhibition of FoxO4 and subsequent contractile protein induction. Although adiponectin and rapamycin have similarly beneficial effects on VSMC phenotype in both cell and organ culture, a direct comparison of the effects of rapamycin versus adiponectin on endothelial cells revealed distinct differences: rapamycin inhibited Akt phosphorylation, whereas adiponectin maintained it. Importantly, Akt activity preserves endothelial function. Conclusion— Adiponectin promotes VSMC differentiation and preserves endothelial cell Akt signaling, suggesting that targeting the adiponectin pathway may have advantages over rapamycin in developing new drug-eluting stent therapeutics.