Therapeutic Potential of the Deubiquitinase BRCC3 in Attenuating Ischemic Myocardial Injury and Ventricular Remodeling

Abstract

The transforming growth factor-β1 (TGF-β1)/Smad3 pathway drives DNA damage, necrosis, and ventricular remodeling following acute myocardial infarction (AMI); however, effective therapies targeting this cascade remain limited. Here, we investigated the role of the deubiquitinating enzyme BRCA1/BRCA2-containing complex subunit 3 (BRCC3) in postinfarction cardiac remodeling and dysfunction using a mouse AMI model established via left coronary artery ligation. The cardiac structure and function were evaluated by echocardiography, Western blotting, and histomorphometry. We found that cardiac BRCC3 expression was markedly down-regulated after AMI. Cardiac-specific BRCC3 overexpression inhibited TGF-β1/Smad3 activation, reduced the infarct size, attenuated adverse remodeling and DNA double-strand breaks, improved cardiac function, and enhanced survival, whereas cardiac-specific Brcc3 gene knockout exacerbated these phenotypes. In vitro, BRCC3 suppressed TGF-β1-induced hypertrophic gene expression and DNA damage in cardiomyocytes, as well as profibrotic responses in cardiac fibroblasts. Mechanistically, BRCC3 bound to the MH2 domain of Smad3 and removed K63-linked polyubiquitination at lysine 333 (K333), thereby inhibiting Smad3 phosphorylation at Ser423/425. Collectively, these findings demonstrate that BRCC3 protects against ischemic injury and pathological remodeling by deubiquitinating Smad3 at K333 to antagonize TGF-β1/Smad3 signaling, identifying BRCC3 as a potential therapeutic target for preventing post-AMI heart failure.