Rapamycin and Adiponectin in Vascular Smooth Muscle Cells: Implications in the Development of Drug-Eluting Stents

Statement of the problem. Drug-eluting stents (DES) dramatically reduce the incidence of coronary restenosis, a frequent complication of percutaneous coronary interventions in the treatment of obstructive arterial diseases. However, they have been reported to be associated with late-stent thrombosis, a potentially fatal complication partially due to inhibited re-endothelialization by rapamycin, a DES reagent which effectively inhibits restenosis.;Methods. We used a combination of pharmacologic agents, siRNA, and overexpression approaches, and compared the effects of rapamycin and adiponectin in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). We also tested whether VSMCs express functional adiponectin both in vitro and in vivo.;Results. (I) Rapamycin induces human coronary artery smooth muscle cell (hCASMC) differentiation via IRS-1-PI3K-Akt2 feedback signaling. Recombinant adiponectin in the HMW or trimeric, but not globular forms induces hCASMC differentiation through a similar mechanism to rapamycin. Adiponectin activates AMPKalpha2, leading to inhibition of mTORC1 and S6K1. This in turn stabilizes IRS-1, driving Akt2 activation, FoxO4 inhibition, and subsequent contractile protein induction. While 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 ECs revealed distinct differences: rapamycin inhibited, while adiponectin maintained, Akt phosphorylation. Importantly, Akt activity preserves endothelial function. (II) hCASMCs express and secrete functional adiponectin, which can be induced by PPARgamma agonist. Knocking down endogenous adiponectin reveals that it is important in maintaining basal contractile protein expression. Adiponectin is also detected in the media layer of intact mouse aorta. Overexpressing adiponectin in hCASMCs induces contractile protein expression via autocrine and paracrine actions.;Conclusions. (I) Adiponectin promotes VSMC differentiation and preserves EC Akt signaling, suggesting that targeting the adiponectin pathway may have advantages over rapamycin in developing new DES therapeutics. (II) VSMC-derived adiponectin may play important roles in maintenance of the VSMC differentiated phenotype, which could contribute to its cardioprotective functions.