Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells

• Published in: Nature communications Vol. 8; no. 1; pp. 1467 - 19
• Main Authors: Das, Sadhan, Senapati, Parijat, Chen, Zhuo, Reddy, Marpadga A, Ganguly, Rituparna, Lanting, Linda, Mandi, Varun, Bansal, Anita, Leung, Amy, Zhang, Selena, Jia, Ye, Wu, Xiwei, Schones, Dustin E, Natarajan, Rama
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.11.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Angiotensin; Angiotensin II; Angiotensin II - metabolism; Animals; Aorta - cytology; Aorta - pathology; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Azepines - pharmacology; Binding sites; Cells, Cultured; Clonal deletion; CRISPR; Enhancers; Gene expression; Gene Expression Regulation; Genes; Histones - metabolism; Hypertension; Hypertension - drug therapy; Hypertension - genetics; Hypertrophy; Inflammation; Kinases; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - pathology; Rats; Rats, Sprague-Dawley; RNA, Long Noncoding - genetics; Signal Transduction - genetics; Signaling; Smooth muscle; Transcription factors; Triazoles - pharmacology
• ISSN: 2041-1723; 2041-1723
• 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.