title: Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation.
abstract: OBJECTIVE
  Tumour protein p53 plays an important role in the vascular remodelling process as well as in oncogenesis. p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a non-genotoxic activator of the p53 pathway. So far, the effect of MDM2 inhibition on vascular remodelling has not been elucidated. We therefore investigated the effect of nutlin-3 on neointima formation.
  
  
  RESULTS
  Nutlin-3 up-regulated p53 and its downstream target p21 in vascular smooth muscle cells (VSMCs). DNA synthesis assay and flow cytometric analysis revealed that nutlin-3 inhibited platelet-derived growth factor (PDGF)-induced VSMC proliferation by cell cycle arrest. This inhibitory effect was abrogated in p53-siRNA-transfected VSMCs. Furthermore, nutlin-3 inhibited PDGF-stimulated VSMC migration. Treatment with nutlin-3 attenuated neointimal hyperplasia at 28 days after vascular injury in mice, associated with up-regulation of p53 and p21. BrdU incorporation was decreased at 14 days after injury in nutlin-3-treated mice. TUNEL assay showed that nutlin-3 did not exaggerate apoptosis of the injured vessels. Infiltration of macrophages and T-lymphocytes and mRNA expression of chemokine (C-C motif) ligand-5, interleukin-6, and intercellular adhesion molecule-1 were decreased in the injured vessels of nutlin-3-treated mice. Nutlin-3 suppressed NF-κB activation in VSMCs, but not in p53-siRNA-transfected VSMCs.
  
  
  CONCLUSIONS
  The MDM2 antagonist nutlin-3 inhibits VSMC proliferation, migration, and NF-κB activation, and also attenuates neointimal hyperplasia after vascular injury in mice, which is associated with suppression of vascular cell proliferation and an inflammatory response. Targeting MDM2 might be a potential therapeutic strategy for the treatment of vascular proliferative diseases.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.forename: Jiro
authors.initials: J
authors.lastname: Ikeda
authors.forename: Eriko
authors.initials: E
authors.lastname: Narabayashi
authors.forename: Hirohide
authors.initials: H
authors.lastname: Matsuura
authors.forename: Ryohei
authors.initials: R
authors.lastname: Miyazaki
authors.forename: Keita
authors.initials: K
authors.lastname: Inanaga
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takeda
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006965:Hyperplasia; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D058426:Neointima / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D007093:Imidazoles; D016328:NF-kappa B; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2