BET Bromodomain Blockade Mitigates Intimal Hyperplasia in Rat Carotid Arteries

EBioMedicine. 2015 Sep 28;2(11):1650-61. doi: 10.1016/j.ebiom.2015.09.045. eCollection 2015 Nov.


Background: Intimal hyperplasia is a common cause of many vasculopathies. There has been a recent surge of interest in the bromo and extra-terminal (BET) epigenetic "readers" including BRD4 since the serendipitous discovery of JQ1(+), an inhibitor specific to the seemingly undruggable BET bromodomains. The role of the BET family in the development of intimal hyperplasia is not known.

Methods: We investigated the effect of BET inhibition on intimal hyperplasia using a rat balloon angioplasty model.

Results: While BRD4 was dramatically up-regulated in the rat and human hyperplastic neointima, blocking BET bromodomains with JQ1(+) diminished neointima in rats. Knocking down BRD4 with siRNA, or treatment with JQ1(+) but not the inactive enantiomer JQ1(-), abrogated platelet-derived growth factor (PDGF-BB)-stimulated proliferation and migration of primary rat aortic smooth muscle cells. This inhibitory effect of JQ1(+) was reproducible in primary human aortic smooth muscle cells. In human aortic endothelial cells, JQ1(+) prevented cytokine-induced apoptosis and impairment of cell migration. Furthermore, either BRD4 siRNA or JQ1(+) but not JQ1(-), substantially down-regulated PDGF receptor-α which, in JQ1(+)-treated arteries versus vehicle control, was also reduced.

Conclusions: Blocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases.

Keywords: BET; BET, bromo- and extra-terminal domain family of epigenetic readers; BRD4; BRD4, bromodomain-containing protein 4, a BET family member; EC, vascular endothelial cells; Epigenetic reader; IH, intimal hyperplasia; Intimal hyperplasia; JQ1(+), a BET-specific bromodomain inhibitor; JQ1(−), inactive enantiomer; PDGF, platelet-derived growth factor; SMC, vascular smooth muscle cell; Smooth muscle cell.

Publication types

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

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Carotid Arteries / drug effects
  • Carotid Arteries / metabolism*
  • Carotid Arteries / pathology*
  • Cell Movement / drug effects
  • Cell Proliferation
  • Cell Survival
  • Cytokines / metabolism
  • Endothelial Cells / drug effects
  • Humans
  • Hyperplasia
  • Immunohistochemistry
  • Inflammation Mediators / metabolism
  • Male
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Interaction Domains and Motifs
  • Rats
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Triazoles / pharmacology
  • Tunica Intima / drug effects
  • Tunica Intima / metabolism*
  • Tunica Intima / pathology*
  • Veins / metabolism
  • Veins / pathology


  • (+)-JQ1 compound
  • Azepines
  • Cytokines
  • Inflammation Mediators
  • Nuclear Proteins
  • Transcription Factors
  • Triazoles
  • Receptor, Platelet-Derived Growth Factor alpha