Emerging evidence has indicated that BRCC36-mediated K63-linked ubiquitination modification was involved in diverse cellular functions,including endocytosis,apoptosis and DNA damage repair. We previously showed that activation of c GMP / PKG pathway contributed to the binding of BRCC36 and the pro-fibrotic factor Smad3. The current study tested the hypothesis that BRCC36 functions as a negative regulator of transforming growth factor-beta( TGF-β) / Smad3 pathway and participates in cardiac remodeling. In isolated adult mouse cardiac fibroblasts,we have demonstrated that TGF-β1 treatment significantly increased the expression of BRCC36. Overexpression BRCC36 suppressed TGF-β1-induced Smad3 phosphorylation,nuclear translocation,extracellular matrix molecular expression and cell proliferation. On the contrary,silencing BRCC36 by transfection of adenovirus-carrying BRCC36 sh RNA potentiated to enhance the pro-fibrotic effect of TGF-β. In vivo,under chronic pressure overload condition-induced by transverse aortic constriction,myocardial pro-survival protein Bcl-2 and Mcl-1 expression were significantly decreased and the pro-apoptosis protein Puma was increased. However,the cardiac-specific over-expression of BRCC36 significantly increased myocardial Bcl-2 and Mcl-1 and inhibited Puma expression. Interestingly,we also found that sustained pressure overload resulted in a significant myocardial DNA injury in wild type mice,which was characterized by the increase of γH2AX level. However,cardiac-specific BRCC36 over-expression significantly decreased the level of γH2AX in the pressure overloaded heart in the transgenic mice,while effectively enhanced myocardial RAD51 expression,a marker of DNA damage repair. Furthermore,BRCC36 over-expression effectively attenuated TAC-induced cardiac fibrosis and remodeling in the transgenic mice,compared with the wild type mice. Collectively,the results have suggested that BRCC36 effectively protected heart against chronic pressure overload-induced cardiac remodeling though antagonizing TGF-β / Smad3 pathway and enhancing myocardial DNA injury repair response. Emerging evidence has indicated that BRCC36-mediated K63-linked ubiquitination modification was involved in diverse cellular functions, including endocytosis, apoptosis and DNA damage repair. We previously showed that contributed cGMP / PKG pathway contributed to the binding of BRCC36 and the pro- The current study tested the hypothesis that BRCC36 functions as a negative regulator of transforming growth factor-beta (TGF-β) / Smad3 pathway and participates in cardiac remodeling. In isolated adult mouse cardiac fibroblasts, we have demonstrated that TGF- β1 treatment significantly increased the expression of BRCC36. Overexpression BRCC36 suppressed TGF-β1-induced Smad3 phosphorylation, nuclear translocation, extracellular matrix molecular expression and cell proliferation. On the contrary, silencing BRCC36 by transfection of adenovirus-carrying BRCC36 sh RNA potentiated to enhance the pro-fibrotic effect of TGF-β. In vivo, under chronic pressure overload condition-i nduced by transverse aortic constriction, myocardial pro-survival protein Bcl-2 and Mcl-1 expression were significantly decreased and the pro-apoptosis protein Puma was increased. However, the cardiac-specific over-expression of BRCC36 significantly enhanced myocardial Bcl-2 and Interestingly, we also found that sustained pressure overload resulted in a significant myocardial DNA injury in wild type mice, which was characterized by the increase of γH2AX level. However, cardiac-specific BRCC36 over-expression significantly decreased the level of γH2AX in the pressure overloaded heart in the transgenic mice, while significantly enhanced myocardial RAD51 expression, a marker of DNA damage repair. Furthermore, BRCC36 over-expression effectively attenuated TAC-induced cardiac fibrosis and remodeling in the transgenic mice, compared with the wild type mice. Collectively, the results have suggested that BRCC36 effectively protected heart against chronic pressure ov erload-induced cardiac remodeling though antagonizing TGF-β / Smad3 pathway and enhancing myocardial DNA injury repair response.