Abstract 954: Novel Mechanism of Adiponectin Cardioprotection Following Myocardial Ischemic/Reperfusion
We and others have recently demonstrated that myocardial ischemia/reperfusion (MI/R) injury is markedly enhanced in adiponectin knockout (Adp−/−) mice. However, the signaling mechanisms responsible for adiponectin’s cardioprotection remain unknown. Since oxidative/nitrative stress has been shown to play an essential role in MI/R injury, we thought to test a hypothesis that lack of Adp may increase MI/R injury by promoting the production of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). Adp−/− or their littermates were subjected to 30 min of MI followed by 3 or 24 (for infarct size determination only) hours of R. Myocardial infarct size and apoptosis, production of peroxynitrite (ONOO−), nitric oxide (NO) and superoxide (O2−), and expression of iNOS and gp91phox were compared. Consistent with our previous findings, MI/R-induced apoptosis and infarct size were markedly enhanced in Adp−/− mice (P<0.01 vs. Adp+/+). Formation of ONOO−, a highly cytotoxic RNS, and its two reaction components, NO and O2−, were all significantly higher in I/R cardiac tissue obtained from Adp−/− than Adp+/+ (P<0.01). Moreover, MI/R-induced gp91phox (a component of NADPH oxidase) expression was further enhanced in Adp−/− mice. Most interestingly, eNOS phosphorylation was significantly reduced but iNOS expression was further increased in I/R tissue from Adp7−/− mice. To further establish a causative link between enhanced oxidative/nitrative stress and exaggerated MI/R injury observed in Adp−/− mice, recombinant globular domain of adiponectin (gAd, 2 μg/g BW, ip.) was administered 10 minutes before R. Impressively, replenishment with gAd reduced MI/R-induced iNOS and gp91phox expression, decreased NO and O2− production, blocked ONOO− formation, and reversed pro-apoptotic and infarct-enlargement effects observed in Adp−/− mice (P<0.01). Taken together, our study demonstrated for the first time that adiponectin is a natural molecule that inhibits iNOS and NADPH oxidase expression and resultant oxidative/nitrative stress. Reduced adiponectin concentration as is observed in type 2 diabetes may render cardiomyocytes more susceptible to I/R injury by deregulating expression of inflammatory genes and enhancing ROS and RNS production.