Pleckstrin homology-like domain family A, member 3 (PHLDA3) has a particularly critical role in regulating cell survival under stress conditions. However, whether PHLDA3 plays a role in myocardial ischemia/reperfusion injury has not been studied. We aimed to assess the possible role of PHLDA3 in myocardial ischemia/reperfusion (I/R) injury. PHLDA3 expression was increased in myocardial tissue from rats with myocardial I/R injury and rat cardiomyocytes with hypoxia/reoxygenation (H/R) injury. PHLDA3 knockdown protected against myocardial I/R injury in vivo and H/R injury in vitro. Inhibition of PHLDA3 increased the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) associated with regulation of the Akt/glycogen synthase kinase-3β (GSK-3β) axis. Repression of Nrf2 reversed PHLDA3-inhibition-mediated cardioprotective effects. Taken together, our work demonstrates that PHLDA3 inhibition exerts a protective role in myocardial I/R injury via regulation of the Akt/GSK-3β/Nrf2 axis. We suggest PHLDA3 as an attractive target for developing treatments against myocardial I/R injury.

中文翻译：

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PHLDA3 抑制通过 Akt/Nrf2 轴减轻氧化应激和炎症反应来防止心肌缺血/再灌注损伤

Pleckstrin 同源性结构域家族 A，成员 3 (PHLDA3) 在压力条件下调节细胞存活方面具有特别关键的作用。然而，尚未研究PHLDA3是否在心肌缺血/再灌注损伤中起作用。我们旨在评估 PHLDA3 在心肌缺血/再灌注 (I/R) 损伤中的可能作用。PHLDA3 在心肌 I/R 损伤大鼠和缺氧/复氧 (H/R) 损伤大鼠心肌细胞的心肌组织中表达增加。PHLDA3 敲低可防止体内心肌 I/R 损伤和体外 H/R 损伤。PHLDA3 的抑制增加了与 Akt/糖原合酶激酶-3β (GSK-3β) 轴的调节相关的核因子红细胞衍生的 2 相关因子 2 (Nrf2) 的激活。抑制 Nrf2 可逆转 PHLDA3 抑制介导的心脏保护作用。总之，我们的工作表明 PHLDA3 抑制通过调节 Akt/GSK-3β/Nrf2 轴在心肌 I/R 损伤中发挥保护作用。我们建议 PHLDA3 作为开发心肌 I/R 损伤治疗方法的有吸引力的靶点。