Mettl14 Attenuates Cardiac Ischemia/Reperfusion Injury by Regulating Wnt1/β-Catenin Signaling Pathway.

Abstract

N6-methyladenosine (m6A) methylation in RNA is a dynamic and reversible modification regulated by methyltransferases and demethylases, which has been reported to participate in many pathological processes of various diseases, including cardiac disorders. This study was designed to investigate an m6A writer Mettl14 on cardiac ischemia-reperfusion (I/R) injury and uncover the underlying mechanism. The m6A and Mettl14 protein levels were increased in I/R hearts and neonatal mouse cardiomyocytes upon oxidative stress. Mettl14 knockout (Mettl14+/-) mice showed pronounced increases in cardiac infarct size and LDH release and aggravation in cardiac dysfunction post-I/R. Conversely, adenovirus-mediated overexpression of Mettl14 markedly reduced infarct size and apoptosis and improved cardiac function during I/R injury. Silencing of Mettl14 alone significantly caused a decrease in cell viability and an increase in LDH release and further exacerbated these effects in the presence of H2O2, while overexpression of Mettl14 ameliorated cardiomyocyte injury in vitro. Mettl14 resulted in enhanced levels of Wnt1 m6A modification and Wnt1 protein but not its transcript level. Furthermore, Mettl14 overexpression blocked I/R-induced downregulation of Wnt1 and β-catenin proteins, whereas Mettl14+/- hearts exhibited the opposite results. Knockdown of Wnt1 abrogated Mettl14-mediated upregulation of β-catenin and protection against injury upon H2O2. Our study demonstrates that Mettl14 attenuates cardiac I/R injury by activating Wnt/β-catenin in an m6A-dependent manner, providing a novel therapeutic target for ischemic heart disease.

• Authors: Ping Pang, Zhezhe Qu, Shuting Yu, Xiaochen Pang, Xin Li, Yuelin Gao, Kuiwu Liu, Qian Liu, Xiuzhu Wang, Yu Bian, Yingqi Liu, Yingqiong Jia, Zhiyong Sun, Hanif Khan, Zhongting Mei, Xiaoqian Bi, Changhao Wang, Xinda Yin, Zhimin Du, Weijie Du
• Journal: Frontiers in cell and developmental biology (Front Cell Dev Biol) Vol. 9 Pg. 762853 ( 2021) ISSN: 2296-634X [Print] Switzerland
• PMID: 35004673 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Pang, Qu, Yu, Pang, Li, Gao, Liu, Liu, Wang, Bian, Liu, Jia, Sun, Khan, Mei, Bi, Wang, Yin, Du and Du.