New insights into the central sympathetic hyperactivity post-myocardial infarction: Roles of METTL3-mediated m6 A methylation.

Abstract

Ventricular arrhythmias (VAs) triggers by sympathetic nerve hyperactivity contribute to sudden cardiac death in myocardial infarction (MI) patients. Microglia-mediated inflammation in the paraventricular nucleus (PVN) is involved in sympathetic hyperactivity after MI. N6-methyladenosine (m6 A), the most prevalent mRNA and epigenetic modification, is critical for mediating cell inflammation. We aimed to explore whether METTL3-mediated m6 A modification is involved in microglia-mediated sympathetic hyperactivity after MI in the PVN. MI model was established by left coronary artery ligation. METTL3-mediated m6 A modification was markedly increased in the PVN at 3 days after MI, and METTL3 was primarily located in microglia by immunofluorescence. RNA-seq, MeRIP-seq, MeRIP-qPCR, immunohistochemistry, ELISA, heart rate variability measurements, renal sympathetic nerve activity recording and programmed electrical stimulation confirmed that the elevated toll-like receptor 4 (TLR4) expression by m6 A modification on TLR4 mRNA 3'-UTR region combined with activated NF-κB signalling led to the overwhelming production of pro-inflammatory cytokines IL-1β and TNF-α in the PVN, thus inducing the sympathetic hyperactivity and increasing the incidence of VAs post-MI. Targeting METTL3 attenuated the inflammatory response and sympathetic hyperactivity and reduced the incidence of VAs post-MI.

• Authors: Lei Qi, Hui Hu, Ye Wang, Hesheng Hu, Kang Wang, Pingjiang Li, Jie Yin, Yugen Shi, Yu Wang, Yuepeng Zhao, Hangji Lyu, Meng Feng, Mei Xue, Xinran Li, Yan Li, Suhua Yan
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 26 Issue 4 Pg. 1264-1280 (02 2022) ISSN: 1582-4934 [Electronic] England
• PMID: 35040253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Methyltransferases
• METTL3 protein, human

Topics

• Animals
• Heart
• Humans
• Methylation
• Methyltransferases (metabolism)
• Myocardial Infarction (complications, genetics, metabolism)
• Paraventricular Hypothalamic Nucleus (metabolism)
• Rats
• Sympathetic Nervous System (metabolism)