BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure.
BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure.
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DOI：
10.1126/scitranslmed.aah5084
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发表时间：
2017-05-17
影响因子：
17.1
通讯作者：
Haldar SM
中科院分区：
文献类型：
--
作者：
Duan Q;McMahon S;Anand P;Shah H;Thomas S;Salunga HT;Huang Y;Zhang R;Sahadevan A;Lemieux ME;Brown JD;Srivastava D;Bradner JE;McKinsey TA;Haldar SM
尽管目前的护理标准，心脏衰竭（HF）初步诊断后的平均5年死亡率约为40%，反映了对新治疗方法的迫切需求。先前的研究表明，表观遗传阅读蛋白含溴结构域蛋白4（BRD 4）是癌症中的一个新兴治疗靶点，在心肌细胞肥大期间作为病理基因反式激活的关键共激活因子发挥作用。然而，这些发现与人类疾病的治疗相关性仍然未知。我们证明，BET布罗莫结构域抑制剂JQ 1的治疗具有治疗效果，在严重的，预先建立的HF从长期的压力超负荷，以及在小鼠大面积前壁心肌梗死后。此外，JQ 1有效地阻断人诱导多能干细胞衍生的心肌细胞（iPSC-CM）中激动剂诱导的肥大。跨动物模型和人iPSC-CM的综合转录组学分析揭示，BET抑制优先阻断常见病理基因调控程序的反式激活，所述常见病理基因调控程序稳健地富集NFκB和TGF-β信号传导网络，典型为先天性炎症和促纤维化心肌基因。正如这些特定的转录机制所预测的那样，我们发现JQ 1在小鼠游泳模型中不抑制生理性心脏肥大。这些发现证实，在染色质水平上靶向先天性炎症和促纤维化心肌信号传导网络的靶向药物在动物模型和人类心肌细胞中是有效的，为进一步开发BET抑制剂和其他用于HF的表观基因组药物提供了关键的理论基础。
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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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
8.8
作者：
Bolden JE;Tasdemir N;Dow LE;van Es JH;Wilkinson JE;Zhao Z;Clevers H;Lowe SW
通讯作者：
Lowe SW
影响因子：
64.5
作者：
Anand P;Brown JD;Lin CY;Qi J;Zhang R;Artero PC;Alaiti MA;Bullard J;Alazem K;Margulies KB;Cappola TP;Lemieux M;Plutzky J;Bradner JE;Haldar SM
通讯作者：
Haldar SM
影响因子：
5.4
作者：
Fatkin, Diane;Seidman, Christine E.;Seidman, Jonathan G.
通讯作者：
Seidman, Jonathan G.