Dexmedetomidine Postconditioning Alleviates Hypoxia/Reoxygenation Injury in Senescent Myocardial Cells by Regulating lncRNA H19 and m6A Modification

Xuan Zhang,Qiang Fu,Weixing Zhao,Yitian Yang,Longhe Xu,Yunliang Zhang,Hao Li,Weidong Mi

doi:10.1155/2020/9250512

Abstract

H19, a long noncoding RNA (lncRNA), reportedly protects myocardial cells (H9c2 cell line) against hypoxia-reoxygenation- (H/R-) induced injury. Dexmedetomidine (Dex) has an important myocardial protective effect, although its function and mechanism in cardiac ischemia/reperfusion (I/R) injury, especially for senile patients, requires further study. RNA N6-methyladenosine (m6A) is the most abundant endogenous RNA modification. However, the effect of Dex postconditioning on RNA m6A modification has rarely been reported. The aim of this study was to evaluate roles of H19 and m6A modification in Dex postconditioning of aged cardiomyocytes. Hydrogen peroxide (H2O2) was used to induce senescence of H9c2 cells. After 6 h of hypoxia, H9c2 cells were exposed to different concentrations of dexmedetomidine (0, 500 nM, 1 μM, and 2 μM) for 6 h. After knockdown or overexpression of H19 and its downstream gene miR-29b-3p and cellular inhibitor of apoptosis protein 1 (cIAP1), Dex postconditioning experiments were performed to examine effects on myocardial cell injury. Global m6A levels after H/R with or without Dex postconditioning were measured with a colorimetric m6A RNA Methylation Quantification Kit. The mechanism by which RNA m6A methylation regulated genes mediating H19 expression was verified by m6A RNA immunoprecipitation (MeRIP), and the function of Dex postconditioning of aged cardiomyocytes was investigated. Dex postconditioning protected against H/R-induced injury of aged myocardial cells through H19/miR-29b-3p/cIAP1, increased methylation of RNA m6A elicited by H/R, and attenuated H/R-induced injury by suppressing expression of the RNA m6A demethylase gene alkB homolog 5 (ALKBH5). In addition, AKLBH5 regulated the expression of H19, and Dex postconditioning attenuated H/R-induced injury via ALKBH5 in aged cardiomyocytes.

Highlights

With the acceleration of global population aging, the morbidity of myocardial infarction (MI) is increasing
We observed that levels of m6A modification increased after exposure to H/R but were decreased following Dex postconditioning in aged H9c2 cells (Figure 6(a))
Levels of m6A modification increased upon exposure to H/R but were decreased following Dex postconditioning in aged H9c2 cells

Summary

Introduction

With the acceleration of global population aging, the morbidity of myocardial infarction (MI) is increasing. Perioperative trauma, stress, and anesthesia increase the risk for I/R injury, especially in elderly patients, whose systemic physiological function is decreased, tolerance to surgery and anesthesia are reduced, and cardiovascular adverse events are incremental [2]. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, protects organs from I/R injury by several mechanisms [3,4,5,6]. As such, it is widely used as anesthesia for cardiovascular surgery; perioperative Dex reportedly reduces the mortality rate at 1 year after surgery, as well as the incidence of postoperative complications and delirium following cardiac surgery [7]. Ischemic postconditioning with Dex reduced the infarct area of adult rat hearts and expression of lactate dehydrogenase, creatine kinase isoenzymes, and malondialdehyde

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