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 buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function.Methods:We used genetic and pharmacologic 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 as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents.Results:Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced 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 pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 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 preconditioning or postconditioning 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 effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance.Conclusions:Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

中文翻译：

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酸敏感离子通道 1a 的治疗抑制可恢复缺血-再灌注损伤后的心脏功能

背景：缺血-再灌注损伤 (IRI) 是与心血管疾病相关的发病率和死亡率相关的主要危险因素之一。在心脏缺血期间，酸性代谢物的积累导致细胞内和细胞外 pH 值降低，可低至 6.0 至 6.5。由此产生的组织酸中毒会加剧缺血性损伤并显着影响心脏功能。方法：我们使用遗传和药理学方法在细胞和全器官水平研究酸敏感离子通道 1a (ASIC1a) 在心脏 IRI 中的作用。人类诱导多能干细胞衍生的心肌细胞以及 IRI 的离体和体内模型用于测试 ASIC1a 抑制剂作为预处理和后处理治疗剂的功效。 结果：ASIC1基因位点与心脑血管缺血性损伤显着相关。使用体外人诱导多能干细胞衍生的心肌细胞和小鼠体外心脏模型，我们证明 ASIC1a 的基因消融可提高急性 IRI 后的心肌细胞活力。使用特定且有效的药理学抑制剂对 ASIC1a 进行治疗性阻断重现了这种心脏保护作用。我们使用心肌梗塞的体内模型和离体供体心脏获取和储存的 2 个模型作为临床模型，以表明 ASIC1a 抑制改善了 IRI 后的心脏活力。使用 ASIC1a 抑制剂作为预处理或后处理剂可提供与基准药物（包括钠-氢交换抑制剂唑尼泊利）等效的心脏保护作用。在细胞和整个器官水平，