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: We used genetic and pharmacological methods to investigate the role of acid sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole organ level. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and post-conditioning therapeutic agents. Results: Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using hiPSC-CMs 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 (MI) 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.

HOPX governs a molecular and physiological switch between cardiomyocyte progenitor and maturation gene programs

“…We initially assessed cellular-level phenotypes using high purity iPSC-derived cardiomyocytes ( Figure 5A ) focusing on HOPX -regulated biological processes ( Figure 3D-G ). Based on HOPX down-regulation of HIF-1 signaling we assessed cardiomyocyte sensitivity to hypoxia using a protocol to model ischemia-reperfusion injury in vitro (Redd et al, 2021). hiPSC-CMs were incubated under hypoxic conditions (0.5% O 2 ) for 18 hours followed by four hours under normoxic conditions.…”

Acid-sensing ion channels as potential therapeutic targets

“…Ligustrazine and A-317567 were found to suppress acid-evoked pain in an angina model in rats and led to reduced cardiac infarct sizes [86]. Strikingly, Hi1a application protected mouse hearts against ischemic-reperfusion injury and rat hearts in a preclinical model of heart donation [87], supporting the emerging notion that ASIC1a represents a possible target in cardiac pathophysiology.…”

Acid-Sensing Ion Channels: Expression and Function in Resident and Infiltrating Immune Cells in the Central Nervous System

“…Finally, and perhaps most importantly, the train of cell-death signaling set off by the initial activation of ASIC1a continues regardless of the subsequent state of the channel. This includes activation of necroptosis (Wang et al, 2015;Redd et al, 2021), apoptosis (Song et al, 2019), and the stimulation of cell executioners such as calcium-activated proteases, endonucleases, and PLA 2 due to the increased levels of intracellular Ca 2+ (Yermolaieva et al, 2004;Xiong et al, 2007).…”