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BET acetyl-lysine binding proteins control pathological cardiac hypertrophy.

Authors: Spiltoir, JI  Stratton, MS  Cavasin, MA  Demos-Davies, K  Reid, BG  Qi, J  Bradner, JE  McKinsey, TA 
Citation: Spiltoir JI, etal., J Mol Cell Cardiol. 2013 Oct;63:175-9. doi: 10.1016/j.yjmcc.2013.07.017. Epub 2013 Aug 9.
Pubmed: (View Article at PubMed) PMID:23939492
DOI: Full-text: DOI:10.1016/j.yjmcc.2013.07.017

Cardiac hypertrophy is an independent predictor of adverse outcomes in patients with heart failure, and thus represents an attractive target for novel therapeutic intervention. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) acetyl-lysine reader proteins, was identified in a high throughput screen designed to discover novel small molecule regulators of cardiomyocyte hypertrophy. JQ1 dose-dependently blocked agonist-dependent hypertrophy of cultured neonatal rat ventricular myocytes (NRVMs) and reversed the prototypical gene program associated with pathological cardiac hypertrophy. JQ1 also blocked left ventricular hypertrophy (LVH) and improved cardiac function in adult mice subjected to transverse aortic constriction (TAC). The BET family consists of BRD2, BRD3, BRD4 and BRDT. BRD4 protein expression was increased during cardiac hypertrophy, and hypertrophic stimuli promoted recruitment of BRD4 to the transcriptional start site (TSS) of the gene encoding atrial natriuretic factor (ANF). Binding of BRD4 to the ANF TSS was associated with increased phosphorylation of local RNA polymerase II. These findings define a novel function for BET proteins as signal-responsive regulators of cardiac hypertrophy, and suggest that small molecule inhibitors of these epigenetic reader proteins have potential as therapeutics for heart failure.


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CRRD Object Information
CRRD ID: 9586348
Created: 2014-09-29
Species: All species
Last Modified: 2014-09-29
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.