Epigenetic Regulation Of T-tubules In Right Heart Failure Induced By Increasing Afterload In The Neonatal Stage
Lincai Ye, Shoubao Wang, Chuan Jiang, Jinfen Liu, Haifa Hong.
Shanghai Children's Medical Center, Shanghai, China.
Background Right ventricular(RV) failure severely compromises the prognosis of many congenital heart disease(CHD) children. However little is known about how RV failure is epigenetically regulated. Here we used CHD associated RV failure model- neonatal rat pulmonary arterial banding(PAB), and most common cyanotic CHD- Tetralogy of Fallot(TOF) to reveal the role of histone transferase CBP/p300 in the control of transverse tubules(T-tubules) of RV cardiomyocytes. Methods and Results. PAB performed on P0 significantly increased RV afterload, which induced RV hypertrophy on P7 and RV failure on P28. Compared with normal RV, RV with heart failure displayed reduced T-tubules and T-tubules associated genes JPH2, Cav3. Calcium imaging indicated contraction amplitude of RV cardiomyocytes significantly decreased and time to peak increased. Similar results were found in cardiomyocytes of TOF. Lower expression of histone transferases CBP/p300 and H3K27ac were observed both in PAB induced RV and TOF hearts. Mosaic deletion of CBP/p300 with AAV-cTnT-Cre in RV resulted lower expression of H3K27ac in RV cardiomyocytes, lost of T-tubules, T-tubules associated genes, and contraction ability of cardiomyocytes. Conclusions Histone transferases CBP/p300 directly regulated T-tubules of RV cardiomyocytes and its histone transferase activity plays an important role in the maintaining of T-tubules in the process CHD RV failure development.
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