USP28 Serves as A Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart [RNA-seq]

The majority of diabetics are susceptible to cardiac dysfunction and heart failure, while conventional drug therapy cannot correct diabetic cardiomyopathy (DCM) progression. Herein, we assessed the potential role and therapeutic value of ubiquitin-specific protease 28 (USP28) on the metabolic vulnerability of DCM. cardiac USP28 deficient diabetic mice showed cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared to their controls. Conversely, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Mechanistically, USP28 directly interacted with peroxisome proliferator-activated receptor a (PPARa), deubiquitinating and stabilizing PPARa (Lys152) to promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects. Overall design: To evaluate function of USP28 overexpression in diabetic heart failure and cardiac remodeling, recombinant adeno-associated virus serotype 9 carrying USP28 under cTnT promoter (rAAV9-cTnT-USP28) was injected into db/db mice to evaluate the effects of USP28 overexpression on DCM.