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Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. Here we show that the proton-gated acid-sensing ion channel 1a (ASIC1a) plays a key role during cardiac ischemia and demonstrate that ASIC1a is a promising therapeutic target to improve the tolerance of cardiac tissue to IRI. Genetic ablation of ASIC1a leads to improved functional recovery following global myocardial IRI in ex vivo mouse hearts, and this effect can be recapitulated by therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors. We used two models of ex vivo donor heart procurement and storage, an in vivo model of myocardial infarction, and in vitro studies using human iPSC-derived cardiomyocytes to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as pre- or post-conditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of donor hearts exposed to myocardial ischemia.

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