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BETting on a new heart failure treatment
Heart failure remains a common and difficult-to-treat medical condition with a high mortality, and there is a great need for more effective therapeutics. Duan et al. determined that a small molecule called JQ1, which was originally developed for cancer therapy, may be an effective treatment for heart failure. Bromodomain-containing protein 4, a member of the BET family of epigenetic regulators and the target of JQ1, plays a role in the development of heart failure and contributes to cardiomyocyte hypertrophy. The authors used a combination of mouse and human induced pluripotent stem cell–derived cardiomyocyte models to show that JQ1 can reverse the detrimental effects of this protein and improve cardiac structure and function even in the setting of prolonged and severe disease. They also found that JQ1 did not interfere with physiological cardiac hypertrophy that occurs in response to exercise, supporting the safety of this approach.
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.
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