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MG53 E3 Ligase-dead Mutant Protects Diabetic Hearts from Acute Ischemic/Reperfusion Injury and Ameliorates Diet-induced Cardiometabolic Damage

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posted on 29.11.2021, 18:05 by Han Feng, Hao Shen, Matthew J Robeson, Yue-Han Wu, Hong-Kun Wu, Geng-Jia Chen, Shuo Zhang, Peng Xie, Li Jin, Yanyun He, Yingfan Wang, Fengxiang Lv, Xinli Hu, Yan Zhang, Rui-Ping Xiao
Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading cause of death, highlighting a major unmet medical need. Over the last decade, MG53, also named TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity that mediates metabolic disorders. Here, we show that an E3 ligase-dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic side-effects. When administrated in normal animals, both recombinant human wild type MG53 protein (rhMG53-WT) and its E3 ligase-dead mutant (rhMG53-C14A) protect the heart equally from myocardial infarction and ischemia/reperfusion (I/R) injury. However, in diabetic db/db mice, rhMG53-WT treatment markedly aggravates hyperglycemia, cardiac I/R injury and mortality, whereas acute and chronic treatment of rhMG53-C14A still effectively ameliorates I/R-induced myocardial injury and mortality or diabetic cardiomyopathy, respectively, without inflicting metabolic side-effects. Furthermore, knock-in of MG53-C14A protects 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 counteract metabolic stress, providing a potentially important therapy for the treatment of acute myocardial injuries amidst metabolic disorders, including diabetes and obesity.

Funding

This work was supported by the National Key R&D Program of China (2018YFA0507603, 2018YFA0800701, 2018YFA0800501), and the National Natural Science Foundation of China (31671177, 81630008, 81790621, 31970722, and 31521062).

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