title: miR-223 reverses experimental pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1α, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH.
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: Marie
authors.initials: M
authors.lastname: Le Guen
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: François
authors.initials: F
authors.lastname: Potus
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Vinck
authors.affiliation: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Ranchoux
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: Ian
authors.initials: I
authors.lastname: Johnson
authors.affiliation: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Antigny
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: Eve
authors.initials: E
authors.lastname: Tremblay
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: Sandra
authors.initials: S
authors.lastname: Breuils-Bonnet
authors.affiliation: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Perros
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and.
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.affiliation: Pulmonary Hypertension and Vascular Biology Research Group from the Quebec Heart and Lung Institute, Department of Medicine, Laval University, Quebec City, Quebec, Canada; and Sebastien.Bonnet@criucpq.ulaval.ca.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D016686:Monocrotaline / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D016686:Monocrotaline; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C525067:MIR223, human; C499320:PARP1 protein, human
keywords: DNA damage; HIF-1α; PARP-1; miR-223; pulmonary hypertension