Bet Bromodomain Proteins Are Critical Regulators Of Molecular Reprogramming In Genetic Dilated Cardiomyopathy

Pathologic gene expression is a hallmark of DCM. Mice carrying a human DCM mutation in phospholamban (PLNR9C) develop fibrosis, DCM and premature death. Temporal RNAseq and pathway analysis in PLNR9C mice identified activation of pro-fibrotic gene expression as a key early driver of DCM. Recently, the bromodomain and extraterminal (BET) family of epigenetic reader proteins has been identified as a key regulator of pathologic gene expression in the heart. Using a chemical genetic strategy, we studied the role of BET proteins on the temporal regulation of gene expression in genetic DCM. PLNR9C and age-matched wild type (WT) mice were treated with the BET inhibitor JQ1 or vehicle from 8 (preDCM) to 20-weeks-of-age (advanced DCM). Vehicle-treated PLNR9C mice developed DCM with severely reduced LV function, negative remodeling and LV hypertrophy, which was blunted with JQ1 (fractional shortening 15±3% vs 27±3%, p=7x10-10; LV end diastolic diameter 4.5±0.3mm vs. 3.9±0.3mm, p=1x10-5; LV mass 99±12mg vs. 86±13mg,...