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

• DOI: 10.2337/db21-0322
• Publication Date: 2021-11-29T18:50:16Z
• Authors: 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
• Keywords: Cardioprotection; Diabetic Cardiomyopathy

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