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Sci Transl Med. 2017 May 17;9(390). pii: eaah5084. doi: 10.1126/scitranslmed.aah5084.

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure.

Author information

1
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
2
Institute for Transformative Molecular Medicine and Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA.
3
BioInfo, Plantagenet, Ontario K0B 1L0, Canada.
4
Division of Cardiovascular Medicine, Department of Medicine, and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
5
Division of Cardiology, Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94158, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
7
Division of Cardiology, Department of Medicine, Consortium for Fibrosis Research & Translation, University of Colorado, Anschutz Medical Campus, Denver, CO 80204, USA.
8
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. saptarsi.haldar@gladstone.ucsf.edu.
9
Division of Cardiology, Department of Medicine, and Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, CA 94158, USA.

Abstract

Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.

PMID:
28515341
PMCID:
PMC5544253
DOI:
10.1126/scitranslmed.aah5084
[Indexed for MEDLINE]
Free PMC Article

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