Hye Kyoung Sung, Jialing Tang, Yubin Lei, Khang Nguyen, Eddie Tam, Jun Wu, Ren‐Ke Li, Vincent Richard, Christoph H. Borchers, Lina Antounians, Dylan Burger, Augusto Zani, Gary Sweeney
Despite advances in percutaneous coronary intervention, ischemia-reperfusion (IR) injury remains a major cause of morbidity and mortality. Adiponectin confers broad cardioprotective effects, motivating the development of adiponectin receptor agonists. Here, we investigated the cardioprotective efficacy and mechanisms of ALY688, a synthetic adiponectin receptor agonist peptide, in myocardial IR injury. In a clinically translatable rat IR model, intravenous administration of ALY688 during ischemia together with subcutaneous dosing that continued for 28 days reduced troponin-I levels, cardiomyocyte death, and infarct size, while preserving cardiac function. ALY688 restored autophagic flux, mitigated reactive oxygen species accumulation, and suppressed apoptosis in both IR hearts and hypoxia-reoxygenation (HR)-treated cardiomyocytes. Proteomic profiling revealed that Rab8a, downregulated by IR, was maintained with ALY688 treatment. Notably, ALY688 increased extracellular vesicle (EV) abundance in myocardium and plasma, and EVs from treated animals displayed distinct proteomic signatures enriched in glycolytic and oxidative stress-related proteins. These EVs conferred protection against HR-induced injury in H9c2 and human iPSC-derived cardiomyocytes. CRISPR-mediated Rab8a knockout impaired ALY688-induced EV biogenesis and attenuated the cytoprotective effects of these EVs. Collectively, these findings identify ALY688 as a promising therapeutic that mitigates IR injury via both direct myocardial protection and Rab8a-dependent EV-mediated cardioprotective signalling.