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

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.

In vivo evaluation of bioprinted cardiac patches composed of cardiac-specific extracellular matrix and progenitor cells in a model of pediatric heart failure.

Pediatric patients with congenital heart defects (CHD) often present with heart failure from increased load on the right ventricle (RV) due to both surgical methods to treat CHD and the disease itself. Patients with RV failure often require transplantation, which is limited due to lack of donor availability and rejection. Previous studies investigating the development and in vitro assessment of a bioprinted cardiac patch composed of cardiac extracellular matrix (cECM) and human c-kit + progenitor cells (hCPCs) showed that the construct has promise in treating cardiac dysfunction. The current study investigates in vivo cardiac outcomes of patch implantation in a rat model of RV failure. Patch parameters including cECM-inclusion and hCPC-inclusion are investigated. Assessments include hCPC retention, RV function, and tissue remodeling (vascularization, hypertrophy, and fibrosis). Animal model evaluation shows that both cell-free and neonatal hCPC-laden cECM-gelatin methacrylate (GelMA) patches improve RV function and tissue remodeling compared to other patch groups and controls. Inclusion of cECM is the most influential parameter driving therapeutic improvements, with or without cell inclusion. This study paves the way for clinical translation in treating pediatric heart failure using bioprinted GelMA-cECM and hCPC-GelMA-cECM patches.