Abstract 417: BET Bromodomain Inhibition Blunts Heart Failure Progression and Fibrosis in Genetic Cardiomyopathy

Abstract

Pathologic gene network activation is a hallmark of DCM and HF. We have used a chemical genetic strategy to study the role of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in the regulation of gene expression in DCM. Transgenic mice carrying a human DCM mutation in phospholamban (PLN R9C ) develop profound fibrosis and DCM that progresses to symptomatic HF and early death. Temporal RNA-seq and pathway analysis identified pro-fibrotic gene expression as a key early driver of DCM progression. PLN R9C and age-matched wild type (WT) mice were treated daily with the potent and specific BET inhibitor JQ1 or vehicle from 8-weeks-of-age (preDCM) to 20-weeks-of-age. Vehicle-treated PLN R9C mice developed DCM with severely reduced LV function and negative cardiac remodeling. JQ1-treated PLN R9C mice had substantially better fractional shortening (27% vs. 15%, p=7x10 -10 ) and less negative remodeling (LV end diastolic diameter 3.9mm vs. 4.5mm, p=1x10 -5 ; LV wall thickness 0.69mm vs. 0.62mm, p=6x10 -6 ) compared to PLN R9C vehicle-treated mice at 20-weeks (n=15). Myocardial fibrosis was also significantly reduced by JQ1 (5.8% PLN R9C -JQ1 vs. 18.4% PLN R9C -vehicle, p=3x10 -5 ; n=3). RNA-seq in preDCM mice treated with JQ1 for 2 weeks demonstrated a decrease in pathologic gene activation. JQ1-treated PLN R9C mice versus vehicle treated mice had reduced expression of natriuretic peptides ( Nppa -31%, Nppb -29%; p<0.001), less myosin heavy chain and actin isoform switching (ratio Myh6 / Myh7 PLN R9C -JQ1=12.2; PLN R9C -vehicle=8.8; ratio Actc1 / Acta1 PLN R9C -JQ1=39.3; PLN R9C -vehicle=12.1; p<0.001), and lower pro-inflammatory gene expression ( Tgfb2 -48%, Tgfb3 -41%, Ctgf -21%, Gdf15 -56%; p<0.001). At 20-weeks-of-age, continued treatment with JQ1 resulted in sustained suppression of cytokine expression with 2-fold lower levels of Tgfb2 and Tgfb3 compared to vehicle-treated PLN R9C mice. These data suggest that early induction of pro-fibrotic signaling is a key driver of pathologic remodeling in PLN R9C DCM. This study also identifies epigenetic control of pathologic gene activation by BET bromodomain proteins as a critical mechanism for cardiomyopathy progression and supports BET inhibition as a possible novel therapeutic strategy for HF.