m6A methyltransferase METTL3 contributes to sympathetic hyperactivity post-MI via promoting TRAF6-dependent mitochondrial ROS production

作者：Peijin Yang, Yu Wang, Weili Ge, Yanyan Jing, Hesheng Hu, Jie Yin, Mei Xue, Ye Wang, Xiaolu Li, Xinran Li, Yugen Shi, Jiayu Tan, Yan Li, Suhua Yan · 发表于：Free Radical Biology and Medicine · 年份：2023 · DOI：10.1016/j.freeradbiomed.2023.10.392 · 被引用次数：20 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Ubiquitin and proteasome pathways

OBJECTIVES: N6-methyladenosine (m6A) is the most prevalent post-translational modification in eukaryotic mRNA. Recently, m6A editing modified by methyltransferase-like enzyme 3 (METTL3), the core m6A methyltransferase, has been demonstrated to be involved in cardiac sympathetic hyperactivity. This study aimed to clarify the effects and underlying mechanisms of METTL3 in the paraventricular nucleus (PVN) in mediating sympathetic activity following myocardial infarction (MI). METHODS: We established rat MI models by left anterior descending coronary artery ligation. m6A quantification was performed.The expression of METTL3 and its downstream gene, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), were determined. The functional role of METTL3 in sympathetic hyperactivity and electrical conduction stability were verified by assessing renal sympathetic nerve activity (RSNA), norepinephrine (NE) levels, and programmed electrical stimulation. Rescue experiments were also conducted. The mechanism by which m6A is involved in mitochondrial reactive oxygen species (mROS) production, mediated by TRAF6/ECSIT pathway, was explored in lipopolysaccharide (LPS) treated primary microglial cells. RESULTS: METTL3 was predominantly localized in the microglia and significantly increased within the PVN at 3 days post-MI. Inhibition of METTL3 decreased m6A levels, TRAF6 expression, and mROS production; downregulated sympathoexcitation, indicated by attenuated NE concentration and RS...