title: Bromodomain-Containing Protein 4: The Epigenetic Origin of Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and suppressed apoptosis. Decreased expression of microRNA-204 has been associated to this phenotype. By a still elusive mechanism, microRNA-204 downregulation promotes the expression of oncogenes, including nuclear factor of activated T cells, B-cell lymphoma 2, and Survivin. In cancer, increased expression of the epigenetic reader bromodomain-containing protein 4 (BRD4) sustains cell survival and proliferation. Interestingly, BRD4 is a predicted target of microRNA-204 and has binding sites on the nuclear factor of activated T cells promoter region.
  
  
  OBJECTIVE
  To investigate the role of BRD4 in PAH pathogenesis.
  
  
  RESULTS
  BRD4 is upregulated in lungs, distal PAs, and PASMCs of patients with PAH compared with controls. With mechanistic in vitro experiments, we demonstrated that BRD4 expression in PAH is microRNA-204 dependent. We further studied the molecular downstream targets of BRD4 by inhibiting its activity in PAH-PASMCs using a clinically available inhibitor JQ1. JQ1 treatment in PAH-PASMCs increased p21 expression, thus triggering cell cycle arrest. Furthermore, BRD4 inhibition, by JQ1 or siBRD4, decreased the expression of 3 major oncogenes, which are overexpressed in PAH: nuclear factor of activated T cells, B-cell lymphoma 2, and Survivin. Blocking this oncogenic signature led to decreased PAH-PASMC proliferation and increased apoptosis in a BRD4-dependent manner. Indeed, pharmacological JQ1 or molecular (siRNA) inhibition of BRD4 reversed this pathological phenotype in addition to restoring mitochondrial membrane potential and to increasing cells spare respiratory capacity. Moreover, BRD4 inhibition in vivo reversed established PAH in the Sugen/hypoxia rat model.
  
  
  CONCLUSIONS
  BRD4 plays a key role in the pathological phenotype in PAH, which could offer new therapeutic perspectives for patients with PAH.
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Potus
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Mylène
authors.initials: M
authors.lastname: Vaillancourt
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Alice
authors.initials: A
authors.lastname: Bourgeois
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Johnson
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Laure
authors.initials: L
authors.lastname: Deschamps
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chabot
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Ruffenach
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Henry
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Breuils-Bonnet
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Ève
authors.initials: È
authors.lastname: Tremblay
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nadeau
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lambert
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Renée
authors.initials: R
authors.lastname: Paradis
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada.
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.affiliation: From the Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada. Sebastien.bonnet@criucpq.ulaval.ca.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: epigenomics; human BRD4 protein; microRNA; pulmonary hypertension; vascular remodeling