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.