METTL3, m6A modification, and EGR1: interplay affecting myocardial I/R injury outcomes.

Autor: Huang C; Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China., Zhang X; Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China., Wu SX; Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China., Chang Q; Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China., Zheng ZK; Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China., Xu J; Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China. fccxuj@zzu.edu.cn.
Jazyk: angličtina
Zdroj: Cell biology and toxicology [Cell Biol Toxicol] 2024 Dec 21; Vol. 41 (1), pp. 7. Date of Electronic Publication: 2024 Dec 21.
DOI: 10.1007/s10565-024-09937-7
Abstrakt: The occurrence of severe myocardial ischemia/reperfusion (I/R) injury is associated with the clinical application of reestablishment technique for heart disease, and understanding its underlying mechanisms is currently an urgent issue. Prior investigations have demonstrated the potential enhancement of MIRI through EGR1 suppression, although the precise underlying regulatory pathways require further elucidation. The core focus of this investigation is to examine the molecular pathways through EGR1 regulates mitophagy-mediated myocardial cell pyroptosis and its impact on MIRI. Cardiomyocyte hypoxia/reoxygenation (H/R) injury models and mouse models of myocardial I/R injury were used to investigate the involvement of EGR1 in regulating mitophagy-mediated myocardial cell pyroptosis in myocardial I/R injury. The research outcomes demonstrated that under H/R conditions, EGR1 expression was upregulated and inhibited the JAK2/STAT3 pathway, leading to enhanced mitophagy and disrupted mitochondrial fusion/fission dynamics, ultimately resulting in myocardial cell pyroptosis. Further research revealed that the upregulation of EGR1 expression was mediated by methyltransferase like 3 (METTL3)-mediated m6A modification of EGR1 mRNA and depended on the binding of insulin like growth factor 2 mrna binding protein 2 (IGF2BP2) to the N6-methyladenosine (m6A) modification site to enhance mRNA stability. In vivo animal experiments confirmed that METTL3 upregulated EGR1 expression through IGF2BP2 and suppressed activation of the janus kinase 2 (JAK2) /signal transducer and activator of transcription 3 (STAT3) pathway, thereby inhibiting mitophagy, disrupting mitochondrial dynamics, promoting myocardial cell pyroptosis, and exacerbating I/R injury.
Competing Interests: Declarations. Ethical statement: All procedures involving animals were approved by the Institutional Animal Care and Use Committee of The First Affiliated Hospital of Zhengzhou University. Consent for publication: Not applicable. Conflict of interest: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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