title: Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension.
abstract: Nuclear factor kappa B (NF-kB)-mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra-terminal (BET) proteins are essential for the expression of a subset of NF-kB-induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down-regulate the expression of selected genes.
  
  
  
  The effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin-dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription-quantitative PCR (RT-qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients.
  
  
  
  JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1-. JQ1+ decreased NF-kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration-dependent decrease in HPMEC proliferation compared with JQ1--treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip) and CDKN2D (p19INK4D) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum-stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients.
  
  
  
  Inhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH.
authors.affiliation: Vascular Biology, Imperial College London, London, UK.|Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Mumby
authors.affiliation: Vascular Biology, Imperial College London, London, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gambaryan
authors.affiliation: Vascular Biology, Imperial College London, London, UK.
authors.forename: Chao
authors.initials: C
authors.lastname: Meng
authors.affiliation: Faculty of Medicine, South Paris University, Clamart, France.|Pulmonary Hypertension: Pathophysiology and Therapeutic Innovation, INSERM Research Unit 999, Clamart, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Perros
authors.affiliation: Faculty of Medicine, South Paris University, Clamart, France.|Pulmonary Hypertension: Pathophysiology and Therapeutic Innovation, INSERM Research Unit 999, Clamart, France.|Pulmonary Resuscitation Respiratory and Service, National Reference Centre for Pulmonary Hypertension Severe, Assistance Publique Hôpitaux de Paris, Hôpital Antoine Béclère, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Vascular Biology, Imperial College London, London, UK.
authors.forename: S John
authors.initials: SJ
authors.lastname: Wort
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
mesh_terms: D001381:Azepines / Q000494:pharmacology; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011652:Pulmonary Circulation; D014230:Triazoles / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D016209:Interleukin-8; D016328:NF-kappa B; D011506:Proteins; D014230:Triazoles; C561695:(+)-JQ1 compound; C508606:CXCL8 protein, human; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins
keywords: bromodomain and extra-terminal proteins; human pulmonary microvascular endothelial cells; inflammation; proliferation; pulmonary hypertension