title: Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats.
abstract: OBJECTIVE
  Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity).
  
  
  RESULTS
  PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 μM PFT.
  
  
  CONCLUSIONS
  Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis.
authors.affiliation: INSERM U999, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; INSERM U1046, Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Jacquin
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
authors.forename: V
authors.initials: V
authors.lastname: Rincheval
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
authors.forename: B
authors.initials: B
authors.lastname: Mignotte
authors.affiliation: INSERM U1046, Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Richard
authors.affiliation: INSERM U999, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: M
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: O
authors.initials: O
authors.lastname: Mercier
authors.affiliation: Telomeres & Cancer laboratory, labeled "Ligue contre le Cancer", UMR3244, Institut Curie, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Londoño-Vallejo
authors.affiliation: Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: E
authors.initials: E
authors.lastname: Fadel
authors.affiliation: INSERM U1046, Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Eddahibi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D016686:Monocrotaline; C121565:pifithrin