Therapeutic inhibition of acid sensing ion channel 1a recovers heart function after ischemia-reperfusion injury

ABSTRACT: Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0–6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. Methods and Results: We show that acid sensing ion channel 1a (ASIC1a) plays a key role during cardiac ischemia and demonstrate that ASIC1a is a novel therapeutic target to improve the tolerance of cardiac tissue to IRI. Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cerebrovascular ischemic injuries. Using human pluripotent stem cell derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and two models of ex vivo donor heart procurement and storage as clinical models 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. Conclusions: Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat) Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Myocardial Ischemia

SUBMITTER: Melanie White  

LAB HEAD: Melanie White

PROVIDER: PXD024581 | Pride | 2022-11-01

REPOSITORIES: Pride