CBP/CREB Regulates the Proliferation and Apoptosis of Cardiomyocytes by Interacting With SERCA

Abstract

Tetralogy of Fallot (TOF) is a common congenital heart disease. In this study, we proposed that cAMP response element-binding protein (CREB)-binding protein (CBP) regulates the proliferation and apoptosis in TOF by interacting with the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA). To confirm this, we collected right ventricle tissue samples from TOF patients during surgery to correct the deformity and from the donors. We performed IHC, IF, RT-qPCR, WB and ChIP experiments. The analysis of these experiments shows that the expression of CBP is higher in TOF patients than in healthy individuals. Further, the RT-qPCR results indicated that the CBP and SERCA mRNA in TOF patients were significantly higher than in the healthy donors. Similarly, WB results suggested that the expression of CBP and SERCA was predominantly elevated in TOF patients compared to healthy individuals. Further, the AC16 cell line with CBP knockdown reveals high expression of the Edu compared to normal cells, and the percentage of the cell cycle in the M phase was elevated in the CBPi group. In addition, the CCK-8 cell viability assay showed more proliferation in the CBPi group than in the control group at different time points. Moreover, the RT-qPCR results indicated a lower expression of SERCA after the knockdown of CBP and CREB. Finally, the ChIP assay shows that CREB binds to the promoter of SERCA, and the CBP enrichment decreased after the CREB knockdown. In conclusion, these results suggest that CBP interacts with SERCA to regulate cell proliferation and apoptosis during heart development and that up-regulation of CBP leads to TOF.