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

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.

• Authors: Qiming Duan, Sarah McMahon, Priti Anand, Hirsh Shah, Sean Thomas, Hazel T Salunga, Yu Huang, Rongli Zhang, Aarathi Sahadevan, Madeleine E Lemieux, Jonathan D Brown, Deepak Srivastava, James E Bradner, Timothy A McKinsey, Saptarsi M Haldar
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 390 (05 17 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 28515341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017, American Association for the Advancement of Science.

Chemical References

• (+)-JQ1 compound
• Azepines
• NF-kappa B
• Proteins
• Transforming Growth Factor beta
• Triazoles
• bromodomain and extra-terminal domain protein, human

Topics

• Animals
• Azepines (therapeutic use)
• Cardiomegaly (drug therapy, genetics, metabolism)
• Gene Regulatory Networks (genetics, physiology)
• Heart Failure (drug therapy, genetics, metabolism)
• Humans
• Induced Pluripotent Stem Cells (metabolism)
• Inflammation (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism)
• NF-kappa B (metabolism)
• Proteins (genetics, metabolism)
• Signal Transduction
• Transforming Growth Factor beta (metabolism)
• Triazoles (therapeutic use)