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Simultaneous Measurement of Superoxide/Hydrogen Peroxide and NADH Production by Flavin-containing Mitochondrial Dehydrogenases
Published on: February 24, 2018
Flavin-containing monooxygenase 2 confers cardioprotection in ischemia models through its disulfide bond catalytic
Qingnian Liu1,2, Jiniu Huang1,2, Hao Ding1,2
1Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Abstract:
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.
Insights
Flavin-containing monooxygenase 2 (FMO2) protects heart cells from death after myocardial infarction (MI). Overexpressing FMO2 reduces cardiac dysfunction, highlighting its therapeutic potential for ischemic heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Oxidative Protein Folding
Background:
- Myocardial infarction (MI) causes significant cardiomyocyte (CM) death and cardiac dysfunction, necessitating novel cardioprotective therapies.
- Current therapeutic strategies for ischemic heart disease are limited in their ability to prevent CM death and restore cardiac function.
Purpose of the Study:
- To investigate the role of flavin-containing monooxygenase 2 (FMO2) in cardiomyocyte survival and cardiac function following ischemic injury.
- To elucidate the underlying molecular mechanisms by which FMO2 exerts cardioprotection.
Main Methods:
- Utilized ex vivo and in vivo models of ischemic injury, including genetic deletion and overexpression of FMO2 in cardiomyocytes.
- Investigated the impact of FMO2 on endoplasmic reticulum (ER) stress pathways, apoptotic proteins (caspase 12, CHOP), and oxidative protein folding.
- Employed a GVSG-mutated FMO2 to assess the role of its chaperone activity in protection.
- Validated findings using human induced pluripotent stem cell-derived CMs.
Main Results:
- FMO2 levels were upregulated in cardiomyocytes following ischemic injury.
- Genetic deletion of FMO2 exacerbated CM death and cardiac dysfunction, while FMO2 overexpression conferred protection.
- FMO2 inhibited ER stress-induced apoptosis by downregulating the unfolded protein response pathway.
- FMO2 functions as a chaperone, catalyzing disulfide bond formation in unfolded proteins via its GVSG motif, which is crucial for its protective function.
- FMO2 demonstrated protective effects in human iPSC-derived CMs.
Conclusions:
- FMO2 plays a critical protective role in cardiomyocytes against ischemic injury.
- FMO2 acts as a chaperone, facilitating oxidative protein folding and mitigating ER stress-induced apoptosis.
- FMO2 represents a promising therapeutic target for treating ischemic heart disease and improving cardiac function post-MI.
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