Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
Nat Commun. 2017 Nov 13;8(1):1467. doi: 10.1038/s41467-017-01629-7.
Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases. Moreover, CRISPR-Cas9-mediated deletion of candidate enhancers/SEs, targeting SEs with the bromodomain and extra-terminal domain inhibitor JQ1, or knockdown of overlapping long noncoding RNAs (lncRNAs) blocks AngII-induced genes associated with growth-factor signaling and atherosclerosis. Furthermore, JQ1 ameliorates AngII-induced hypertension, medial hypertrophy and inflammation in vivo in mice. These results demonstrate AngII-induced signals integrate enhancers/SEs and lncRNAs to increase expression of genes involved in VSMC dysfunction, and could uncover novel therapies.
血管紧张素 II（AngII）通过激活血管平滑肌细胞（VSMCs）中的促生长和促炎基因表达，促进高血压和动脉粥样硬化。增强子和超级增强子（SEs）在驱动与疾病相关的基因表达方面发挥着关键作用。然而，介导 VSMC 功能障碍的增强子/SEs 仍未被描述。在这里，我们表明 AngII 在体外、离体和 AngII 输注的小鼠主动脉体内改变了培养的 VSMCs 中的血管增强子和 SE 谱。AngII 诱导的增强子/SEs 富含信号依赖性转录因子结合位点，并依赖于关键信号激酶。此外，CRISPR-Cas9 介导的候选增强子/SEs 缺失、针对 SE 的溴结构域和额外末端结构域抑制剂 JQ1 的靶向治疗，或重叠长非编码 RNA（lncRNA）的敲低，可阻断与生长因子信号和动脉粥样硬化相关的 AngII 诱导基因。此外，JQ1 可改善 AngII 诱导的高血压、体内小鼠中膜肥厚和炎症。这些结果表明 AngII 诱导的信号整合增强子/SEs 和 lncRNAs 以增加参与 VSMC 功能障碍的基因表达，并可能揭示新的治疗方法。
