Artesunate Inhibits Myocardial Ischemia Reperfusion Injury via Downregulation of Lysine Specific Demethylase 5A

ABSTRACT Myocardial ischemia–reperfusion (MI/R) injury can lead to heart disease. Meanwhile, Artesunate (ART) inhibits the severity of I/R‐induced myocardial injury. Nevertheless, the underlying mechanism of ART in MI/R remains unclear. In vivo and in vitro experiments were performed to investigate the function of ART in MI/R. TTC, H&E, and TUNEL assays were applied for assessing myocardial injury and apoptosis. CCK‐8, flow cytometry, and ELISA were applied for testing cell viability, apoptosis, and the levels of MDA, ROS, CK, and LDH, respectively. ChIP, dual luciferase assay, and RNA pull‐down were performed to explore the relation among KDM5A, miR‐495‐3p, and FOXO1. ART dramatically attenuated I/R‐induced myocardial injury in mice, and it inhibited the I/R‐caused increase of ROS, MDA, CK, and LDH in mice. Additionally, ART notably alleviated hypoxia/reoxygenation (H/R)‐induced cardiomyocyte injury through inhibition of histone demethylase KDM5A, and KDM5A promoted H/R‐induced injury in cardiomyocytes via downregulating miR‐495‐3p. Meanwhile, FOXO1 was identified as the downstream mRNA of miR‐495‐3p, and miR‐495‐3p reversed H/R‐induced cardiomyocyte injury through downregulating FOXO1. Silencing of KDM5A attenuated I/R‐induced myocardial injury by directly upregulating miR‐495‐3p in mice. ART alleviates MI/R injury via modulating KDM5A/miR‐495‐3p/FOXO1. Thus, this study might provide a new strategy against MI/R.