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

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.

SUBMITTER: Wang J

PROVIDER: S-EPMC8109143 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m<sup>6</sup>A modification of ATF4 mRNA.

Wang Jiayi J Zhang Jiehan J Ma Yan Y Zeng Yuxiao Y Lu Cheng C Yang Fenghua F Jiang Nianxin N Zhang Xuan X Wang Yuhua Y Xu Yinghui Y Hou Hanjing H Jiang Shengyang S Zhuang Shaowei S

Aging 20210326 8

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m<sup>6</sup>A 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 a ...[more]

PMID: 33819187

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Project description:BackgroundThe modification of N6-methyladenosine (m6A) is a dynamic and reversible course that might play a role in cardiovascular disease. However, the mechanisms of m6A modification in myocardial ischemia/reperfusion injury (MIRI) remain unclear.MethodsA mouse model of MIRI and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) HL-1 cells were employed. In an in vivo study, the total RNA m6A modification levels were determined by dot blot, and the key genes related to m6A modification were screened by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. In an in vitro study, the effects of AlkB homolog 5 (ALKBH5), an RNA demethylase, on cell proliferation, cell injury, and apoptosis were detected by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, lactate dehydrogenase (LDH) and cardiac troponin-I (cTnI) levels, and flow cytometry. Besides, the m6A modification-changed and differentially expressed messenger RNA (mRNA) were determined by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) in ALKBH5-overexpressed HL-1 cells. Finally, the mRNA levels of the promising targeted gene were examined by RT-qPCR and its m6A modification levels were examined by MeRIP-qPCR.ResultsOur results showed that RNA m6A modification was involved in MIRI, in which ALKBH5 was downregulated. Functionally, by overexpressing or silencing ALKBH5 in experimental cells, we verified its protective properties on cell proliferation, cell injury, and apoptosis in the process of MIRI. Besides, we provided a mass of latent different mRNAs with m6A modification variation in ALKBH5-overexpressed HL-1 cells. Mechanistically, we further screened the most potential targeted mRNAs and suggested that triple functional domain (Trio) mRNA could be upregulated by ALKBH5 by reducing m6A level of Trio.ConclusionsThis study demonstrated that the downregulated ALKBH5 might contribute to MIRI process by increasing the m6A modification of Trio mRNA and downregulating Trio.

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

Publications

WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m<sup>6</sup>A modification of ATF4 mRNA.

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

Publications

WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m<sup>6</sup>A modification of ATF4 mRNA.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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