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Author Notes:

Rui-Ping Xiao, Email: xiaor@pku.edu.cn Yan Zhang, Email: zhangyan9876@pku.edu.cn

H.F., H.S., Y.Z., and R.-P.X. proposed the hypothesis, generated the initial idea, conducted key experiments, and wrote the manuscript. Y.Z. and R.-P.X. designed the study, supervised the experiments and data analysis, wrote the manuscript, and interpreted the results. M.J.R., Y.-H.W., H.-K.W., F.L., and X.H. researched data and contributed to discussion. G.-J.C., S.Z., P.X., L.J., Y.H., and Y.W. researched data. Y.Z. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors thank Drs. H.P. Cheng for insightful discussions and H. Shang, W. Zheng, W.Q. Zhang, and X.T. Sun for excellent technical support. The authors also thank Drs. H. Takeshima and J.J. Ma for providing the Mg53−/− mice.

No potential conflicts of interest relevant to this article were reported.

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Research Funding:

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:

  • Animals
  • Cells, Cultured
  • Cytoprotection
  • Diabetic Cardiomyopathies
  • Diet, High-Fat
  • Female
  • Heart
  • Humans
  • Male
  • Membrane Proteins
  • Metabolic Syndrome
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardial Reperfusion Injury
  • Myocardium
  • Myocytes, Cardiac
  • Signal Transduction

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

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Journal Title:

Diabetes

Volume:

Volume 71, Number 2

Publisher:

, Pages 298-314

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2022 by the American Diabetes Association

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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