BET acetyl-lysine binding proteins control pathological cardiac hypertrophy
Open accessAbstract
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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In mice with pressure-overload heart failure, BET inhibition with JQ1 strongly protected left ventricular ejection fraction.
“BET inhibition exerted a strong protective effect on left ventricular ejection fraction (Fig. 1B)4,6-10.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [7]
The Results report that JQ1 rescued pressure-overload-induced left ventricular systolic dysfunction in mice subjected to transverse aortic constriction, as assessed by echocardiography. The available Results passage does not identify ejection fraction as the measure or quantify the strength of its protection, so those specifics are not verified. (LLM, conf=0.82)
Experimental — accuracy not yet measuredBET proteins act as transcriptional co-activators, and their inhibition is linked to protection in heart failure models.
“As BET proteins are transcriptional co-activators and their inhibition is associated with protection in heart failure models6-8”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [7]
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Self-citation
- Authors
- Spiltoir, J. I., Stratton, M. S., Cavasin, M. A., Demos-Davies, K., Reid, B. G., Qi, J., Bradner, J. E., & McKinsey, T. A.
- Affiliations
- University of Colorado Anschutz (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- McKinsey, Timothy A.
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 63
- Pages
- 175-179
- ISSN
- 0022-2828 (ISSN-L)
- PMC
- PMC4089995
- OpenAlex
- W2002730815
- Cited by
- 174
- References
- 14
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 14 · 2023: 10 · 2022: 14 · 2021: 13 · 2020: 21 · 2019: 18 · 2018: 14 · 2017: 9 · 2016: 16 · 2015: 11 · 2014: 14 · 2013: 1
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Molecular and Cellular Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R21AG043822)
- National Heart, Lung, and Blood Institute (R01HL116848, T32HL007822)
- National Institute of General Medical Sciences (T32GM007635)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- cardiac hypertrophy, BET proteins, JQ1, BRD4, BRD2, BRD3, BRDT, heart failure, left ventricular hypertrophy, transverse aortic constriction, atrial natriuretic peptide, RNA polymerase II phosphorylation, epigenetic regulation, cardiomyocyte hypertrophy, small molecule inhibitors
- MeSH terms
- Animals, Azepines, Carrier Proteins, Cardiomegaly, Models, Biological, Protein Binding, Triazoles, Rats, Drug Discovery, High-Throughput Screening Assays
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