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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism*
  • Animals
  • Aorta / cytology
  • Aorta / pathology
  • Atherosclerosis / drug therapy
  • Atherosclerosis / genetics*
  • Azepines / pharmacology
  • Cells, Cultured
  • Gene Expression Regulation
  • Histones / metabolism
  • Hypertension / drug therapy
  • Hypertension / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / pathology*
  • Myocytes, Smooth Muscle / pathology*
  • RNA, Long Noncoding / genetics*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / genetics
  • Triazoles / pharmacology


  • (+)-JQ1 compound
  • Azepines
  • Histones
  • RNA, Long Noncoding
  • Triazoles
  • Angiotensin II