Inhibition of ALPK1 attenuates myocardial ischemia-reperfusion injury in Nur77-deficient mice via suppressing XPO1-dependent pathway.

Abstract

Despite being the initial intervention of choice, revascularization for myocardial ischemia-reperfusion (I/R) injury remains constrained, making the exploration of novel therapeutic targets imperative. Alpha-kinase 1 (ALPK1) knockdown mitigates ischemic brain injury, whereas its function in cardiac I/R injury requires further investigation. Nur77 knockout (Nur77 KO) mice, with more severe post-acute myocardial infarction (post-AMI) cardiac dysfunction, fibrosis and hypertrophy than C57BL/6 mice, underwent 45 min LAD ligation plus 4 h reperfusion for modeling and genetic ALPK1 knockdown's impacts on this injury were examined in hypoxic AC16 cardiomyocytes via siRNA silencing, pharmacological ferroptosis rescue and siRNA-resistant ALPK1 plasmid functional recovery assays. The results demonstrated that genetic ALPK1 knockdown resulted in an improvement in cardiac function, the amelioration of pathological changes, a reduction in infarct size, and the suppression of apoptosis of myocardial cells in Nur77 KO mice post-I/R. Furthermore, genetic ALPK1 knockdown was observed to suppress lipid peroxidation and ferroptosis, while concomitantly activating Nrf2/HO-1 pathway in Nur77 KO mice post-I/R. Furthermore, genetic ALPK1 knockdown was observed to inhibit apoptosis and ferroptosis in vitro and pharmacological rescue experiments confirmed ferroptosis as the core downstream cell death pathway of ALPK1. ALPK1 was observed to interact with XPO1, thereby inhibiting XPO1 degradation. Moreover, XPO1 overexpression impeded the impact of ALPK1 knockdown on cell survival, lipid peroxidation, and ferroptosis. ALPK1 represents a potential novel target for pharmacological intervention in the treatment of myocardial I/R injury.