USP28-regulated mitochondrial homeostasis mechanism that involves the PPARa-Mfn2 axis in diabetic hearts [ChIP-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. PPARa-/- in the db/db background mice were constructed to check the mechanism of USP28 in vivo. Inducible cardiac-specific deletion of Mfn2 in the db/db background mice was utilized to evaluate USP28-mediated cardioprotection. chromatin immunoprecipitation (ChIP) assays revealed that PPARa promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects. Overall design: The interaction of PPARa and Mfn2 promoter was verified by chromatin immunoprecipitation (ChIP) assay in hiPSC-CMs