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m6A methyltransferase WTAP regulates myocardial ischemia reperfusion injury through YTHDF1/FOXO3a signaling

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Abstract

N6-methyladenosine (m6A) is emerging as an essential regulator in the progression of myocardial ischemia reperfusion (I/R) injury. However, the in-depth functions and mechanisms for m6A are still unclear. This work aimed to explore the potential functions and mechanisms for myocardial I/R injury. In this study, m6A methyltransferase WTAP and m6A modification level elevated in the hypoxia/reoxygenation (H/R) induced rat cardiomyocytes (H9C2) and I/R injury rat model. Bio-functional cellular experiments demonstrated that knockdown of WTAP remarkably released the proliferation and reduced the apoptosis and inflammatory cytokines induced by H/R. Moreover, exercise training alleviated WTAP level in exercise-trained rats. Mechanistically, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed that a remarkable m6A modification site was found in the 3’-UTR of FOXO3a mRNA. Moreover, WTAP triggered the installation of m6A modification on FOXO3a mRNA through m6A reader YTHDF1, thereby enhancing the stability of FOXO3a mRNA. Collectively, WTAP/YTHDF1/m6A/FOXO3a axis regulates the myocardial I/R injury progression, which provides new insights for the treatment of myocardial injury.

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  1. Hui Wang, Liujing Fu and Yin Li are first author.

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  1. Department of Cardiology, Tianjin Fourth Central Hospital, Tianjin, 300140, China

    Hui Wang, Liujing Fu, Yin Li, Liudong Wei, Xiufeng Gu, Huanming Li, Jie Li & Shangyu Wen

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Wang, H., Fu, L., Li, Y. et al. m6A methyltransferase WTAP regulates myocardial ischemia reperfusion injury through YTHDF1/FOXO3a signaling. Apoptosis 28, 830–839 (2023). https://doi.org/10.1007/s10495-023-01818-4

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