title: BET Bromodomain Blockade Mitigates Intimal Hyperplasia in Rat Carotid Arteries.
abstract: 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.
authors: Department of Surgery, Wisconsin Institute for Medical Research, Madison, WI 53705, USA.
authors: Bowen
authors: B
authors: Wang
authors: Department of Surgery, Wisconsin Institute for Medical Research, Madison, WI 53705, USA.
authors: Mengxue
authors: M
authors: Zhang
authors: Department of Surgery, Wisconsin Institute for Medical Research, Madison, WI 53705, USA; University of Wisconsin Hospital and Clinics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors: Toshio
authors: T
authors: Takayama
authors: Department of Surgery, Wisconsin Institute for Medical Research, Madison, WI 53705, USA.
authors: Xudong
authors: X
authors: Shi
authors: Department of Surgery, Wisconsin Institute for Medical Research, Madison, WI 53705, USA.
authors: Drew Alan
authors: DA
authors: Roenneburg
authors: Department of Surgery, Wisconsin Institute for Medical Research, Madison, WI 53705, USA; University of Wisconsin Hospital and Clinics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors: K Craig
authors: KC
authors: Kent
authors: Department of Surgery, Wisconsin Institute for Medical Research, Madison, WI 53705, USA.
authors: Lian-Wang
authors: LW
authors: Guo
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D014680:Veins / Q000378:metabolism / Q000473:pathology
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D016207:Cytokines; D018836:Inflammation Mediators; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; D020796:Receptor, Platelet-Derived Growth Factor alpha
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