State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA.
Diabetes. 2022 Feb 1;71(2):298-314. doi: 10.2337/db21-0322.
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.
心血管代谢疾病，包括糖尿病及其心血管并发症，是全球主要的死亡原因，凸显出重大未满足的医疗需求。在过去的十年中，肌联蛋白 53（MG53），也称为 TRIM72，已成为心肌膜修复和心脏保护的有力因子，但由于其 E3 连接酶活性介导代谢紊乱，其治疗价值变得复杂。在这里，我们表明 E3 连接酶失活突变体 MG53-C14A 在不引起代谢不良反应的情况下保留其心脏保护功能。在正常动物中给予时，重组人野生型 MG53 蛋白（rhMG53-WT）及其 E3 连接酶失活突变体（rhMG53-C14A）同样可保护心脏免受心肌梗死和缺血/再灌注（I/R）损伤。然而，在糖尿病 db/db 小鼠中，rhMG53-WT 治疗显著加重高血糖、心脏 I/R 损伤和死亡率，而 rhMG53-C14A 的急性和慢性治疗仍可有效改善 I/R 引起的心肌损伤和死亡率或糖尿病心肌病，分别没有代谢不良反应。此外，MG53-C14A 的基因敲入可保护小鼠免受高脂肪饮食引起的代谢紊乱和心脏损伤。因此，E3 连接酶失活突变体 MG53-C14A 不仅可保护心脏免受急性心肌损伤，还可抵抗代谢应激，为治疗代谢紊乱中的急性心肌损伤，包括糖尿病和肥胖症，提供了一种潜在的重要治疗方法。
