MG53 E3 Ligase–Dead Mutant Protects Diabetic Hearts From Acute Ischemic/Reperfusion Injury and Ameliorates Diet-Induced Cardiometabolic Damage

• Type of Material: Article
• Authors: Han Feng, Peking University; Hao Shen, Peking University; Matthew J Robeson, Georgia Institute of Technology; Yue-Han Wu, Peking University; Hong-Kun Wu, Peking University; Geng-Jia Chen, Peking University; Shuo Zhang, Peking University; Peng Xie, Peking University; Jin Li, Peking University; Yanyun He, Peking University; Yingfan Wang, Peking University; Fengxiang Lv, Peking University; Xinli Hu, Peking University; Yan Zhang, Peking University; Rui-Ping Xiao, Peking University
• Language: English
• Date: 2022-02-01
• Publisher: American Diabetes Association
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the American Diabetes Association
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.2337/db21-0322
• Title of Journal or Parent Work: Diabetes
• Volume: 71
• Issue: 2
• Start Page: 298
• End Page: 314
• Grant/Funding Information: This work was supported by the National Key R&D Program of China (2018YFA0507603, 2018YFA0800701, and 2018YFA0800501) and the National Natural Science Foundation of China (31671177, 81630008, 81790621, 31970722, and 31521062).
• Keywords: Male; Signal Transduction; Diet, High-Fat; Mice, Inbred C57BL; Myocardium; Membrane Proteins; Mice; Myocardial Reperfusion Injury; Female; Cytoprotection; Mice, 129 Strain; Mice, Transgenic; Metabolic Syndrome; Humans; Diabetic Cardiomyopathies; Animals; Heart; Cells, Cultured; Myocytes, Cardiac
• Research Categories: Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading causes of death, highlighting a major unmet medical need. Over the past decade, mitsugumin 53 (MG53), also called TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity, which mediates metabolic disorders. Here, we show that an E3 ligase–dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic adverse effects. When administered in normal animals, both the recombinant human wild-type MG53 protein (rhMG53-WT) and its E3 ligase–dead mutant (rhMG53-C14A) protected the heart equally from myocardial infarction and ischemia/reperfusion (I/R) injury. However, in diabetic db/db mice, rhMG53-WT treatment markedly aggravated hyperglycemia, cardiac I/R injury, and mortality, whereas acute and chronic treatment with rhMG53-C14A still effectively ameliorated I/R-induced myocardial injury and mortality or diabetic cardiomyopathy, respectively, without metabolic adverse effects. Furthermore, knock-in of MG53-C14A protected the mice from high-fat diet–induced metabolic disorders and cardiac damage. Thus, the E3 ligase–dead mutant MG53-C14A not only protects the heart from acute myocardial injury but also counteracts metabolic stress, providing a potentially important therapy for the treatment of acute myocardial injury in metabolic disorders, including diabetes and obesity.