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Research Paper|Volume 13, Issue 8|pp 11135—11149

WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA

Jiayi Wang1, Jiehan Zhang1, Yan Ma1, Yuxiao Zeng1, Cheng Lu1, Fenghua Yang1, Nianxin Jiang1, Xuan Zhang1, Yuhua Wang1, Yinghui Xu1, Hanjing Hou1, Shengyang Jiang1, Shaowei Zhuang1
  • 1Department of Cardiology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
* Equal contribution
Received: December 6, 2020Accepted: February 3, 2021Published: March 26, 2021
https://doi.org/10.18632/aging.202770

Copyright: © 2021 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP’s effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.