title: Role for Runt-related Transcription Factor 2 in Proliferative and Calcified Vascular Lesions in Pulmonary Arterial Hypertension.
abstract: Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This is sustained in time by the down-regulation of microRNA (miR)-204. In systemic vascular diseases, reduced miR-204 expression promotes vascular biomineralization by augmenting the expression of the transcription factor Runt-related transcription factor 2 (RUNX2). Implication of RUNX2 in PAH-related vascular remodeling and presence of calcified lesions in PAH remain unexplored.
  
  
  
  We hypothesized that RUNX2 is up-regulated in lungs of patients with PAH, contributing to vascular remodeling and calcium-related biomineralization.
  
  
  
  We harvested human lung tissues in which we assessed calcification lesions and RUNX2 expression. We also isolated PASMCs from these tissues for in vitro analyses. Using a bidirectional approach, we investigated the role for RUNX2 in cell proliferation, apoptosis, and calcification capacity. Ectopic delivery of small interfering RNA against RUNX2 was used in an animal model of PAH to evaluate the therapeutic potential of RUNX2 inhibition in this disease.
  
  
  
  Patients with PAH display features of calcified lesions within the distal pulmonary arteries (PAs). We show that RUNX2 is up-regulated in lungs, distal PAs, and primary cultured human PASMCs isolated from PAH and compared with patients without PAH. RUNX2 expression histologically correlates with vascular remodeling and calcification. Using in vitro gain- and loss-of-function approaches, we mechanistically demonstrate that miR-204 diminution promotes RUNX2 up-regulation and that sustained RUNX2 expression activates hypoxia-inducible factor-1α, leading to aberrant proliferation, resistance to apoptosis, and subsequent transdifferentiation of PAH-PASMCs into osteoblast-like cells. In the PAH Sugen/hypoxia rat model, molecular RUNX2 inhibition reduces PA remodeling and prevents calcification, thus improving pulmonary hemodynamic parameters and right ventricular function.
  
  
  
  RUNX2 plays a pivotal role in the pathogenesis of PAH, contributing to the development of proliferative and calcified PA lesions. Inhibition of RUNX2 may therefore represent an attractive therapeutic strategy for PAH.
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Ruffenach
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chabot
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Virginie F
authors.initials: VF
authors.lastname: Tanguay
authors.affiliation: 2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Courboulin
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boucherat
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Francois
authors.initials: F
authors.lastname: Potus
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Aude
authors.initials: A
authors.lastname: Pflieger
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Sandra
authors.initials: S
authors.lastname: Breuils-Bonnet
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nadeau
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Renée
authors.initials: R
authors.lastname: Paradis
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Eve
authors.initials: E
authors.lastname: Tremblay
authors.affiliation: 2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.affiliation: 2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hautefort
authors.affiliation: 2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.affiliation: 2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: 2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmuller
authors.affiliation: 2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.|2 UMR-S 999, INSERM and University Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.affiliation: 1 Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Department of Medicine, Laval University, Quebec, Canada; and.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000235:genetics* / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D061205:Vascular Calcification / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human
keywords: calcification; hypoxia-inducible factor-1α; pulmonary artery smooth muscle cells; pulmonary hypertension; vascular remodeling