FMO2 (Flavin Containing Monooxygenase 2) Prevents Cardiac Fibrosis via CYP2J3-SMURF2 Axis

作者：Cheng Ni, Yongjian Chen, Yinchuan Xu, Jing Zhao, Qingju Li, Changchen Xiao, Yan Wu, Jingyi Wang, Yingchao Wang, Zhiwei Zhong, Ling Zhang, Rongrong Wu, Qingnian Liu, Xianpeng Wu, Changle Ke, Wei Zhu, Jinghai Chen, Jijun Huang, Yibin Wang, Jianan Wang, Xinyang Hu · 发表于：Circulation Research · 年份：2022 · DOI：10.1161/circresaha.122.320538 · 被引用次数：35 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiac electrophysiology and arrhythmias、Cardiac Ischemia and Reperfusion

Background: Cardiac fibrosis is a common pathological feature associated with adverse clinical outcome in postinjury remodeling and has no effective therapy. Using an unbiased transcriptome analysis, we identified FMO2 (flavin-containing monooxygenase 2) as a top-ranked gene dynamically expressed following myocardial infarction (MI) in hearts across different species including rodents, nonhuman primates, and human. However, the functional role of FMO2 in cardiac remodeling is largely unknown. Methods: Single-nuclei transcriptome analysis was performed to identify FMO2 after MI; FMO2 ablation rats were generated both in genetic level using the CRISPR-cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) technology and lentivirus-mediated manner. Gain-of-function experiments were conducted using postn -promoter FMO2, miR1a/miR133a-FMO2 lentivirus, and enzymatic activity mutant FMO2 lentivirus after MI. Results: A significant downregulation of FMO2 was consistently observed in hearts after MI in rodents, nonhuman primates, and patients. Single-nuclei transcriptome analysis showed cardiac expression of FMO2 was enriched in fibroblasts rather than myocytes. Elevated spontaneous tissue fibrosis was observed in the FMO2-null animals without external stress. In contrast, fibroblast-specific expression of FMO2 markedly reduced cardiac fibrosis following MI in rodents and nonhuman primates associated with ...