Extracellular Vesicles Modulation by an Adiponectin Receptor Agonist Provides Cardioprotection for Myocardial...

Ischemic heart disease is a leading cause of global morbidity and mortality, with more effective clinical therapies needed to mitigate cardiac ischemic injury. Extracellular vesicles (EVs) mediate intercellular communication in cardiac pathophysiology. Adiponectin mediates cardioprotective effects yet its relationship with EVs biology remains unexplored. We investigated whether ALY688, an adiponectin receptor agonist, modulates EV biogenesis and cargo to confer cardioprotection in a mouse model of myocardial infarction (MI). ALY688 (15 mg/kg daily for 28 days) significantly attenuated MI-induced cardiac dysfunction, reduced infarct size, and decreased fibrotic scar in both lean mice on standard chow and obese mice fed a high-fat diet. Plasma EVs were isolated and while MI reduced circulating EV numbers, ALY688 restored EV production and enhanced loading with bioactive adiponectin. In addition, proteomic analysis revealed ALY688-shaped EVs were enriched in metabolism regulated proteins. The direct functional effects and mechanisms of EV action were examined in iPSC-derived cardiomyocytes and H9c2 cells. EV from ALY688 treated mice (EV^ALY) reduced hypoxia-induced apoptosis, cell death, and ROS accumulation while restoring mitochondrial function and enhancing autophagy flux, whereas EV from control mice did not. Importantly, intervention with systemic EV^ALY administration to mice reduced post-MI plasma troponin I and LDH levels, decreased apoptosis, and improved mitochondrial dynamics. Thus, we show that ALY688 enhances EV-mediated cardioprotection through multiple cellular mechanisms including adiponectin delivery, oxidative stress reduction, autophagy restoration, and mitochondrial recovery. These findings provide preclinical evidence supporting the feasibility of evidence for harnessing endogenous repair mechanisms through EVs modulation to mitigate acute cardiovascular injury.