Cardioprotective effect of adiponectin is partially mediated by its AMPK-independent antinitrative action

Wang Y, Tao L, Yuan Y, Lau WB, Li R, Lopez BL, Christopher TA, Tian R, Ma XL. Cardioprotective effect of adiponectin is partially mediated by its AMPK-independent antinitrative action. Am J Physiol Endocrinol Metab 297: E384-E391, 2009. First published May 26, 2009; doi: 10.1152ajpendo.90975.2008.-Adiponectin (APN) exerts its metabolic regulation largely through AMP-dependent protein kinase (AMPK). However, the role of AMPK in APN's antiapoptotic effect in ischemic-reperfused (IR) adult cardiomyocytes remains incompletely understood. The present study was designed to determine the involvement of AMPK in the antiapoptotic signaling of APN. Cardiomyocytes from adult male mice over-expressing a dominant-negative alpha 2-subunit of AMPK (AMPK-DN) or wildtype (WT) littermates were subjected to simulated IR (SIR) and pretreated with 2 mu g/ml globular domain of APN (gAPN) or vehicle. SIR-induced cardiomyocyte apoptosis was modestly increased in AMPK-DN cardiomyocytes (P < 0.05). Treatment with gAPN significantly reduced SIR-induced apoptosis in WT cardiomyocytes as well as in AMPK-DN cardiomyocytes, indicating that the antiapoptotic effect of gAPN is partially AMPK independent. Furthermore, gAPN-induced endothelial nitric oxide synthase (eNOS) phosphorylation was significantly reduced in AMPK-DN cardiomyocytes, suggesting that the APN-eNOS signaling axis is impaired in AMPK-DN cardiomyocytes. Additional experiments demonstrated that treatment of AMPK-DN cardiomyocytes with gAPN reduced SIR-induced NADPH oxidase overexpression, decreased superoxide generation, and blocked peroxynitrite formation to the same extent as that observed in WT cardiomyocytes. Collectively, our present study demonstrated that although the metabolic and eNOS activation effect of APN is largely mediated by AMPK, the superoxide-suppressing effect of APN is not mediated by AMPK, and this AMPK-independent antioxidant property of APN increased nitric oxide bioavailability and exerted significant antiapoptotic effect.