The Importance of Restoring the Adiponectin Signaling Pathway to Reduce Myocardial Reperfusion Injury in Diabetes.

The incidence of heart failure after an acute myocardial infarction (AMI) remains unacceptably high despite medical advances in the past several years (1). Therefore, the discovery of new drugs or strategies to reduce myocardial damage in patients with AMI is urgently warranted. This problem is exacerbated particularly in those affected by diabetes. Diabetes significantly reduces myocardial ischemic tolerance after a sudden coronary artery occlusion, thereby leading to increased ischemic and reperfusion (IR) injuries (2). During the past several years, ischemic postconditioning (IPo) has emerged as an efficient intervention to reduce reperfusion injury and infarct size in patients with AMI (3). It consists of very short repetitive episodes of IR applied at the immediate onset of reperfusion after a prolonged coronary artery occlusion. Unfortunately, previous experimental studies demonstrated that the beneficial effects of IPo are largely lost in the presence of diabetes, although the mechanisms underlying this phenomenon remain to be fully clarified (2). In their study in this issue of Diabetes, Li et al. (4) demonstrate that type 1 diabetes abrogates the beneficial effects of IPo through the disruption of adiponectin signaling. Adiponectin is an adipocytokine that regulates glucose and fatty acid metabolism, exerting antioxidant, antiinflammatory, and pro-survival effects (5). Adiponectin is also synthetized and secreted by cardiomyocytes, protecting against myocardial IR injury (5,6). Li et al. demonstrate that cardiac adiponectin levels are significantly reduced in response to IR, but this effect is dampened by IPo, which upregulates cardiac adiponectin levels in the early phase of reperfusion. IPo significantly reduced IR injury in wild-type mice, whereas it failed to be cardioprotective in systemic adiponectin knockout mice, thereby demonstrating that adiponectin is required for the beneficial effects of IPo. Additionally, it was found that IPo improved mitochondrial function, reduced oxidative stress, and increased nitric oxide levels in an adiponectin-dependent manner. Mechanistically, the beneficial effects of adiponectin in IPo appeared to be specifically mediated by the activation of adiponectin receptor 1 (AdipoR1) but not by AdipoR2, thereby confirming previous results demonstrating that AdipoR1 and AdipoR2 may regulate different mechanisms (7). Of note, IPo also increased the interaction between AdipoR1 and caveolin-3 (Cav3), a protein that appears to be critical for AdipoR1 function. This result is supported by evidence that the beneficial effects of adiponectin are lost in mice with Cav3 gene deletion (8). IPo significantly increased myocardial levels of signal transducer and activator of transcription 3 (STAT3) phosphorylated at Ser, which is known to localize to mitochondria (9). These effects also appear to be mediated by adiponectin and were required for the cardioprotective effects of IPo. Interestingly, the adiponectin/AdipoR1/mitochondrial STAT3 (mitoSTAT3) pathway was found to be disrupted in the hearts of rats with streptozotocin-induced diabetes. IPo failed to be protective and to increase myocardial adiponectin levels during reperfusion in diabetic animals. In addition, Li et al. found that diabetes inhibited IPo-induced AdipoR1-Cav3 interaction. This data suggest that diabetes disrupts adiponectin signaling by affecting both adiponectin levels and AdipoR1 signaling. Several mechanistic aspects of this study remain to be clarified. The signaling pathways through which cardiac adiponectin levels are regulated by IPo and diabetes remain unknown. Previous studies demonstrated that SIRT1 induces adiponectin upregulation through FOXO1-dependent mechanisms (10). Interestingly, SIRT1 signaling protects