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

Ping Pang,Xiaochen Pang,Weijie Du,Xiuzhu Wang,Xinda Yin,Yingqiong Jia,Zhongting Mei,Xin Li,Shuting Yu,Kuiwu Liu,Hanif Khan,Qian Liu,Xiaoqian Bi,Zhezhe Qu,Changhao Wang,Yuelin Gao,Yingqi Liu,Yu Bian,Zhen Sun ,Zhenhong Du

doi:10.3389/fcell.2021.762853

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.

Highlights

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide
In accordance with the previous studies (Jiang et al, 2020), we found that Wnt/β-catenin signaling was suppressed in response to I/R as reflected by the decreased expression level of Wnt1, β-catenin, and Dvl1 and increased the p-β-catenin protein level, which was markedly reversed by Mettl14 overexpression (Figures 6A–D)
We found that Mettl14 protected against cardiac I/R injury as indicated by the reduction in apoptosis, cardiac infarct size, and improvement in cardiac dysfunction

Summary

Introduction

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. The most effective strategies to improve the clinical outcome of AMI patients are early and timely reperfusion therapy including thrombolysis, angioplasty, or bypass surgery by percutaneous coronary intervention. Reperfusion itself can cause damage to the MI heart, indicative of enhanced myocardial infarct size and cell death—a phenomenon termed ischemia–reperfusion (I/R) injury (Gul-Kahraman et al, 2019). The expansion of the infarct area due to I/R injury will. Mettl Regulates Cardiac Ishemia/Reperfusion Injury continually contribute to progressive cardiac remodeling, heart failure, and even sudden cardiac death. Despite the beneficial effects in the attenuation of I/R injury obtained by many pharmacological interventions, the clinical trials have still been disappointing (Krzywonos-Zawadzka et al, 2017; Han et al, 2019). A better understanding of I/R pathogenesis is urgently required to develop the novel therapeutic approach

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Conclusion