Cardiomyocyte-specific deficiency of C/EBPβ aggravates pressure overload-induced heart failure

CCAAT/enhancer-binding protein (C/EBP) β is a member of the basic-leucine zipper transcription factor family that regulates cell differentiation, proliferation, cell death and survival, and inflammation. Although C/EBPβ plays both protective and detrimental roles in the heart at baseline and during stress, the cell-type-specific functions of C/EBPβ in the heart are unknown. Here, we investigated the role of endogenous C/EBPβ in cardiomyocytes during pressure overload (PO)-induced heart failure.

We found that C/EBPβ expression was reduced in wild-type mouse heart homogenates after 4 weeks of transverse aortic constriction (TAC). To elucidate the role of endogenous C/EBPβ during cardiac stress in vivo, we generated cardiomyocyte-specific Cebpb knockout (Cebpb-cKO) mice. Cebpb-cKO mice were born at a normal Mendelian ratio but displayed slightly decreased cardiac function under baseline conditions, starting at 3 months of age. Notably, in contrast to a previous report using systemic heterozygous Cebpb-knockout mice, which exhibited cardiac protection against TAC, Cebpb-cKO mice showed significantly exacerbated systolic dysfunction, cardiac hypertrophy, and fibrosis after 4 weeks of TAC. Cebpb-cKO mice also exhibited decreased expression of antioxidant genes, including Mnsod and Catalase, both at baseline and under TAC conditions. On the other hand, rescue of the C/EBPβ level in cardiomyocytes using AAV9-cTnT-Cebpb alleviated the left ventricular dysfunction in response to TAC.

Our findings suggest that C/EBPβ has a cell-type-specific role in the heart and that endogenous C/EBPβ in cardiomyocytes plays a salutary role during PO.