Ischemia reperfusion injury (IRI) is one of the major risk factors associated with primary graft dysfunction, the leading cause of early mortality in heart transplant recipients. 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 new 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 venom-derived pharmacological inhibitors. Using two models of donor heart procurement and storage, we show that ASIC1a inhibition yields improved post-IRI cardiac viability and function as a pre- or post-conditioning agent, with organ recovery equal to benchmark drugs including the sodium-hydrogen exchange inhibitor, zoniporide. Using human pluripotent stem cells, we show that ASIC1a inhibition improves cardiomyocyte viability under conditions of acidosis or ischemia in vitro . At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors have no impact on cardiac electromechanical coupling and physiological performance. Consistent with a key role for ASIC1a in human cardiac ischemia, we used summary data from GWAS to show that polymorphisms in the ASIC1 genetic locus are strongly associated with susceptibility to cardiac ischemic injuries. 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.Significance Statement Ischemia-reperfusion injury (IRI) is the primary reason for early allograft failure after heart transplantation. IRI is also implicated in the pathophysiology of diverse post-ischemic heart diseases that are a leading cause of morbidity and mortality worldwide. There are currently no drugs available to protect the heart from IRI. This study uses genetic approaches to demonstrate a novel role for ASIC1a in mediating the response of the heart to IRI. In addition, we identify venom-derived ASIC1a inhibitors as novel pharmacological therapeutics for cardiovascular medicine, in particular for the preservation of donor hearts destined for transplantation.

Enhanced donor heart preservation by therapeutic inhibition of acid sensing ion channel 1a