Flavin-containing monooxygenase 2 confers cardioprotection in ischemia models through its disulfide-bond catalytic activity.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-10-31 DOI:10.1172/JCI177077
Qingnian Liu, Jiniu Huang, Hao Ding, Yue Tao, Jinliang Nan, Changchen Xiao, Yingchao Wang, Rongrong Wu, Cheng Ni, Zhiwei Zhong, Wei Zhu, Jinghai Chen, Chenyun Zhang, Xiao He, Danyang Xiong, Xinyang Hu, Jian'an Wang
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Abstract

Myocardial infarction (MI) is characterized by massive cardiomyocytes death and cardiac dysfunction, and effective therapies to achieve cardioprotection are sorely needed. Here we reported that flavin containing monooxygenase 2 (FMO2) level was markedly increased in cardiomyocytes both in ex vivo and in vivo models of ischemia injury. Genetic deletion of FMO2 resulted in reduced cardiomyocyte survival and enhanced cardiac dysfunction, whereas cardiomyocyte-specific FMO2 overexpression exerted a protective effect in infarcted rat hearts. Mechanistically, FMO2 inhibited the activation of endoplasmic reticulum (ER) stress-induced apoptotic proteins, including caspase 12 and C/EBP homologous protein (CHOP), by down-regulating unfolded protein response (UPR) pathway. Furthermore, we identified FMO2 as a chaperone that catalyzed disulfide-bond formation in unfolded/misfolded proteins through its GVSG motif. GVSG-mutated FMO2 failed to catalyze disulfide-bond formation and lost its protection against ER stress and cardiomyocyte death. Finally, we demonstrated the protective effect of FMO2 in human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. Collectively, this study highlights FMO2 as a key modulator of oxidative protein folding in cardiomyocytes and underscores its therapeutic potential for treating ischemic heart disease.

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含黄素单加氧酶2通过其二硫键催化活性在缺血模型中赋予心脏保护作用。
心肌梗死(MI)的特点是心肌细胞大量死亡和心脏功能障碍,因此亟需有效的疗法来实现心脏保护。在这里,我们报告了在体内外缺血损伤模型中,心肌细胞中含黄素单加氧酶2(FMO2)的水平明显升高。基因缺失 FMO2 会导致心肌细胞存活率降低和心脏功能障碍加重,而心肌细胞特异性 FMO2 的过表达对梗死的大鼠心脏有保护作用。从机理上讲,FMO2 通过下调未折叠蛋白反应(UPR)通路,抑制了内质网(ER)应激诱导的凋亡蛋白(包括 Caspase 12 和 C/EBP 同源蛋白(CHOP))的活化。此外,我们还发现FMO2是一种伴侣蛋白,通过其GVSG基序催化未折叠/折叠蛋白中二硫键的形成。GVSG突变的FMO2不能催化二硫键的形成,失去了对ER应激和心肌细胞死亡的保护作用。最后,我们证明了FMO2在人类诱导多能干细胞衍生心肌细胞(hiPSC-CM)模型中的保护作用。总之,本研究强调了FMO2是心肌细胞氧化蛋白折叠的关键调节因子,并突出了其治疗缺血性心脏病的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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