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

  • J Clin Invest. 2024 Oct 31;134(24):e177077. doi: 10.1172/JCI177077.
Qingnian Liu  1  2 ,  Jiniu Huang  1  2 ,  Hao Ding  1  2 ,  Yue Tao  1  2 ,  Jinliang Nan  1  2 ,  Changchen Xiao  1  2 ,  Yingchao Wang  1  2 ,  Rongrong Wu  1  2 ,  Cheng Ni  1  2 ,  Zhiwei Zhong  1  2 ,  Wei Zhu  1  2 ,  Jinghai Chen  3 ,  Chenyun Zhang  1  2 ,  Xiao He  4 ,  Danyang Xiong  4 ,  Xinyang Hu  1  2  5 ,  Jian'an Wang  1  2  5
Affiliations
  • 1. Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2. Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 3. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
  • 5. State Key Laboratory of Transvascular Implantation Devices, Hangzhou, Zhejiang, China.
PMID: 39480513 DOI: 10.1172/JCI177077
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.

Keywords
Cardiology; Cardiovascular disease; Cell stress; Chaperones.