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ITFG2, an immune-modulatory protein, targets ATP 5b to maintain mitochondrial function in myocardial infarction.

Author information

Affiliations

  • 1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
      Authors
    • Bi FF 1
    • Cao M 1
    • Pan QM 1
    • Jing ZH 1
    • Lv LF 1
    • Li TY 1
    • Li XL 1
    • Liang HH 1
    (8 authors)
  • 2. Department of Basic Medicine, Xiamen Medical College, Xiamen, Fujian 361023, PR China.
      Authors
    • Liu F 2
    • Tian H 2
    (2 authors)
  • 3. Shanghai Frontiers Science Research Center for Druggability of Cardiovascular noncoding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering Science, Shanghai 201620, PR China.
      Authors
    • Yu T 3
    • Shan HL 3
    (2 authors)
  • 4. Department of Basic Medicine, Xiamen Medical College, Xiamen, Fujian 361023, PR China; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
      Authors
    • Zhou YH 4
    (1 author)

ORCIDs linked to this article

Biochemical Pharmacology, 06 Jun 2024, 226:116338
https://doi.org/10.1016/j.bcp.2024.116338 PMID: 38848780 

Abstract 

ITFG2, as an immune-modulatory intracellular protein that modulate the fate of B cells and negatively regulates mTORC1 signaling. ITFG2 is highly expressed in the heart, but its pathophysiological function in heart disease is unclear. In this study, we found that in MI mice, overexpression of ITFG2 via an AAV9 vector significantly reduced the infarct size and ameliorated cardiac function. Knockdown of endogenous ITFG2 by shRNA partially aggravated ischemia-induced cardiac dysfunction. In cardiac-specific ITFG2 transgenic (TG) mice, myocardial infarction size was smaller, eject fraction (EF) and fractional shortening (FS) was higher compared to those in wild-type (WT) mice, suggesting ITFG2 reversed cardiac dysfunction induced by MI. In hypoxic neonatal cardiomyocytes (NMCMs), overexpression of ITFG2 maintained mitochondrial function by increasing intracellular ATP production, reducing ROS levels, and preserving the mitochondrial membrane potential (MMP). Overexpression of ITFG2 reversed the mitochondrial respiratory dysfunction in NMCMs induced by hypoxia. Knockdown of endogenous ITFG2 by siRNA did the opposite. Mechanism, ITFG2 formed a complex with NEDD4-2 and ATP 5b and inhibited the binding of NEDD4-2 with ATP 5b leading to the reduction ubiquitination of ATP 5b. Our findings reveal a previously unknown ability of ITFG2 to protect the heart against ischemic injury by interacting with ATP 5b and thereby regulating mitochondrial function. ITFG2 has promise as a novel strategy for the clinical management of MI.

Full text links 

Read article at publisher's site: https://doi.org/10.1016/j.bcp.2024.116338

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