Abstract 18905: Myocyte-Specific Deletion of P300 Prevents Cardiac Hypertrophy Following Pressure Overload in a Mouse Model

Abstract

Background: The lysine acetyltransferases CREB binding protein (CBP, KAT3A) and p300 (KAT3B) are important epigenetic regulators of gene transcription. Both share extensive sequence homology and multiple overlapping functions and properties. However, genetic loss-of-function studies indicate that CBP and p300 have distinct roles in cardiac development. We have previously shown that p300 is a stress-responsive, quantitatively limiting driver of cardiac hypertrophy. Objective: To compare the roles of p300 and CBP in adult cardiac hypertrophy. Methods: Recombination was induced in mice harboring the a-MHC Mer-Cre-Mer transgene and CBP or p300 floxed alleles with tamoxifen (TA) at 10 weeks of age. Pressure overload was induced by transverse aortic coarctation (TAC) and pressure gradients were quantitated by Doppler flow/velocity. Cardiac function was evaluated using echocardiography before and after surgery. Apoptosis and fibrosis was assessed using CardioTACs assay and Masson tri-chrome staining respectively. Myocyte hypertrophy and fibrosis were quantitated by histology at d21 post TAC. Genome-wide transcriptional analysis was performed by microarray and RNASeq. Results: TAC produced myocyte hypertrophy, cardiac enlargement, and systolic dysfunction that was reduced to near sham-operated levels in a gene-dose-dependent manner by loss of p300 (p<0.001 for p300 fl/fl vs p300+/+). Loss of p300 did not impair survival post TAC. Histologically, fibrosis and myocyte apoptosis after TAC were markedly decreased in p300fl/fl vs p300+/+ mice (15.04% vs 38.92%,p<0.001). Remarkably, cardiac systolic function (EF % and FS %) were unimpaired in p300KO mice following TAC. Loss of CBP had no impact on any of these parameters. Transcriptional analysis revealed that loss of CBP had a much greater impact on gene expression than loss of p300, and that relatively few genes were responsive to both p300 and CBP loss. A group of 89 mRNAs and ncRNAs were exclusively sensitive to p300 loss, reflecting an important function in oxidative stress. Conclusions: Cardiac myocyte p300 plays a critical and cell-autonomous role in cardiac hypertrophy and heart failure that is not complemented by CBP. Investigation of p300 specific gene targets is warranted.