PHLDA3 inhibition protects against myocardial ischemia/reperfusion injury by alleviating oxidative stress and inflammatory response via the Akt/Nrf2 axis

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.