title: Role for DNA damage signaling in pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is associated with sustained inflammation known to promote DNA damage. Despite these unfavorable environmental conditions, PAH pulmonary arterial smooth muscle cells (PASMCs) exhibit, in contrast to healthy PASMCs, a pro-proliferative and anti-apoptotic phenotype, sustained in time by the activation of miR-204, nuclear factor of activated T cells, and hypoxia-inducible factor 1-α. We hypothesized that PAH-PASMCs have increased the activation of poly(ADP-ribose) polymerase-1 (PARP-1), a critical enzyme implicated in DNA repair, allowing proliferation despite the presence of DNA-damaging insults, eventually leading to PAH.
  
  
  RESULTS
  Human PAH distal pulmonary arteries and cultured PAH-PASMCs exhibit increased DNA damage markers (53BP1 and γ-H2AX) and an overexpression of PARP-1 (immunoblot and activity assay), in comparison with healthy tissues/cells. Healthy PASMCs treated with a clinically relevant dose of tumor necrosis factor-α harbored a similar phenotype, suggesting that inflammation induces DNA damage and PARP-1 activation in PAH. We also showed that PARP-1 activation accounts for miR-204 downregulation (quantitative reverse transcription polymerase chain reaction) and the subsequent activation of the transcription factors nuclear factor of activated T cells and hypoxia-inducible factor 1-α in PAH-PASMCs, previously shown to be critical for PAH in several models. These effects resulted in PASMC proliferation (Ki67, proliferating cell nuclear antigen, and WST1 assays) and resistance to apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling and Annexin V assays). In vivo, the clinically available PARP inhibitor ABT-888 reversed PAH in 2 experimental rat models (Sugen/hypoxia and monocrotaline).
  
  
  CONCLUSIONS
  These results show for the first time that the DNA damage/PARP-1 signaling pathway is important for PAH development and provide a new therapeutic target for this deadly disease with high translational potential.
authors.affiliation: Department of Medicine, Laval University, Pulmonary Hypertension Research Group, IUCPQ Research Centre, Québec, Canada (J.M., A.P., M.V., F.P., C.G., A.C., S.B.-B., E.T., C.C., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, Canada (R.P., S.Z., E.D.M.).
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.forename: Aude
authors.initials: A
authors.lastname: Pflieger
authors.forename: Mylène
authors.initials: M
authors.lastname: Vaillancourt
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: François
authors.initials: F
authors.lastname: Potus
authors.forename: Sotirios
authors.initials: S
authors.lastname: Zervopoulos
authors.forename: Colin
authors.initials: C
authors.lastname: Graydon
authors.forename: Audrey
authors.initials: A
authors.lastname: Courboulin
authors.forename: Sandra
authors.initials: S
authors.lastname: Breuils-Bonnet
authors.forename: Eve
authors.initials: E
authors.lastname: Tremblay
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D016686:Monocrotaline / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001562:Benzimidazoles; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D050778:NFATC Transcription Factors; C521013:veliparib; D016686:Monocrotaline; C499320:PARP1 protein, human; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: DNA damage; PARP1 protein, human; microRNAs; pulmonary arterial hypertension