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

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 (m A), the most prevalent mRNA and epigenetic modification, is critical for mediating cell inflammation. We aimed to explore whether METTL3-mediated m 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 m 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 m 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.