title: Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension.
abstract: BACKGROUND
  Induction of cellular senescence through activation of the p53 tumor suppressor protein is a new option for treating proliferative disorders. Nutlins prevent the ubiquitin ligase MDM2 (murine double minute 2), a negative p53 regulator, from interacting with p53. We hypothesized that cell senescence induced by Nutlin-3a exerted therapeutic effects in pulmonary hypertension (PH) by limiting the proliferation of pulmonary artery smooth muscle cells (PA-SMCs).
  
  
  RESULTS
  Nutlin-3a treatment of cultured human PA-SMCs resulted in cell growth arrest with the induction of senescence but not apoptosis; increased phosphorylated p53 protein levels; and expression of p53 target genes including p21, Bax, BTG2, and MDM2. Daily intraperitoneal Nutlin-3a treatment for 3 weeks dose-dependently reduced PH, right ventricular hypertrophy, and distal pulmonary artery muscularization in mice exposed to chronic hypoxia or SU5416/hypoxia. Nutlin-3a treatment also partially reversed PH in chronically hypoxic or transgenic mice overexpressing the serotonin-transporter in SMCs (SM22-5HTT+ mice). In these mouse models of PH, Nutlin-3a markedly increased senescent p21-stained PA-SMCs; lung p53, p21, and MDM2 protein levels; and p21, Bax, PUMA, BTG2, and MDM2 mRNA levels; but induced only minor changes in control mice without PH. Marked MDM2 immunostaining was seen in both mouse and human remodeled pulmonary vessels, supporting the use of Nutlins as a PH-targeted therapy. PH prevention or reversal by Nutlin-3a required lung p53 stabilization and increased p21 expression, as indicated by the absence of Nutlin-3a effects in hypoxia-exposed p53(-/-) and p21(-/-) mice.
  
  
  CONCLUSIONS
  Nutlin-3a may hold promise as a prosenescence treatment targeting PA-SMCs in PH.
authors.affiliation: Hôpital Henri Mondor, Service de Physiologie-Explorations Fonctionnelles, Créteil, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mouraret
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.forename: Shariq
authors.initials: S
authors.lastname: Abid
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gary-Bobo
authors.forename: Mirna
authors.initials: M
authors.lastname: Saker
authors.forename: Amal
authors.initials: A
authors.lastname: Houssaini
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Rande
authors.forename: Laurent
authors.initials: L
authors.lastname: Boyer
authors.forename: Jorge
authors.initials: J
authors.lastname: Boczkowski
authors.forename: Geneviève
authors.initials: G
authors.lastname: Derumeaux
authors.forename: Valérie
authors.initials: V
authors.lastname: Amsellem
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology / Q000473:pathology; D011758:Pyrroles / Q000633:toxicity; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016037:Single-Blind Method; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000172:deficiency; D014463:Ultrasonography
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D007211:Indoles; D010879:Piperazines; D011758:Pyrroles; D050486:Serotonin Plasma Membrane Transport Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C116890:Semaxinib