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

中文翻译：

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含黄素的单加氧酶 2 通过其二硫键催化活性在缺血模型中赋予心脏保护


心肌梗死 （MI） 的特征是大量心肌细胞 （CM） 死亡和心功能不全，非常需要有效的疗法来实现心脏保护。在这里，我们报道了在缺血性损伤的离体和体内模型中 CM 中含黄素的单加氧酶 2 （FMO2） 水平显着增加。FMO2 的基因缺失导致 CM 存活率降低和心功能不全增强，而 CM 特异性 FMO2 过表达在梗死大鼠心脏中具有保护作用。从机制上讲，FMO2 通过下调未折叠的蛋白质反应通路来抑制 ER 应激诱导的凋亡蛋白的激活，包括 caspase 12 和 C/EBP 同源蛋白 （CHOP）。此外，我们发现 FMO2 是一种伴侣，通过其 GVSG 基序催化未折叠和错误折叠蛋白中二硫键的形成。GVSG 突变的 FMO2 未能催化二硫键形成，并失去了对 ER 应激和 CM 死亡的保护。最后，我们在人诱导多能干细胞衍生的 CM 模型中证明了 FMO2 的保护作用。总的来说，本研究强调了 FMO2 是 CM 中氧化蛋白折叠的关键调节剂，并强调了其治疗缺血性心脏病的治疗潜力。