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
- 1 Department of Cardiology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
Received: December 6, 2020 Accepted: February 3, 2021 Published: March 26, 2021
https://doi.org/10.18632/aging.202770How to Cite
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.