Abstract 114: AdipoRon, the First Orally Active Adiponectin Receptor Activator, Attenuates Post-ischemic Myocardial Apoptosis via AMPK Activation and Oxidative Stress Reduction

Abstract

Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild type (WT) or gene manipulated mice were treated with vehicle or AdipoRon (50 mg/kg, 10 minutes prior to MI) and subjected to MI/R (30 minutes/3-24 hours). Oral administration of AdipoRon to WT mice significantly improved cardiac function (P<0.01) and reduced infarct size (P<0.01). At cellular level, AdipoRon attenuated post-ischemic cardiomyocyte apoptosis determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (P<0.01). MI/R-induced apoptotic cell death was significantly enhanced in APN deficient mice (APNKO), and AdipoRon attenuated MI/R injury to the same degree observed in WT mice, indicating the pathological exageration caused by APN deficience can be rescured by a small molecule APN receptor activator. Cardiomyocyte-specific inhibition of AMPK (AMPK-DN), the most significant molecule mediating APN’s metabolic regulatory function, also increased post-ischemic apoptosis. Interestingly, AdipoRon’s anti-apoptotic action was partially inhibited, but not lost in AMPK-DN mice, indicating the anti-apoptotic effect of AdipoRon cannot be completely atributed to AMPK activation. AdipoRon significantly attenuated post-ischemic oxidative stress in an AMPK-independent fashion, as evidenced by reduced NADPH oxidase expression and superoxide production in both WT and AMPK-DN mice. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated post-ischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes.