Document Detail


Inhibition of MDM2 Attenuates Neointimal Hyperplasia via Suppression of Vascular Proliferation and Inflammation.
MedLine Citation:
PMID:  21498419     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Aims Tumor protein p53 plays an important role in vascular remodeling process as well as oncogenesis. p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a nongenotoxic activator of the p53 pathway. So far, the effect of MDM2 inhibition on vascular remodeling has not been elucidated. We therefore investigated the effect of nutlin-3 on neointima formation. Methods and Results Nutlin-3 up-regulated p53 and its downstream p21 in VSMCs. DNA synthesis assay and flow cytometric analysis revealed that nutlin-3 inhibited platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell (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 was decreased in the injured vessels of nutlin-3-administered mice. Nutlin-3 suppressed NF-κB activation in VSMCs, but not in p53-siRNA transfected VSMCs. Conclusions MDM2 antagonist nutlin-3 inhibits VSMC proliferation, migration, and NF-κB activation, and also attenuates neointimal hyperplasia after vascular injury in mice, associated with suppression of vascular cell proliferation and inflammatory response. Targeting MDM2 might be a potential therapeutic strategy for the treatment of vascular proliferative diseases.
Authors:
Toru Hashimoto; Toshihiro Ichiki; Jiro Ikeda; Eriko Narabayashi; Hirohide Matsuura; Ryohei Miyazaki; Keita Inanaga; Kotaro Takeda; Kenji Sunagawa
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-14
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
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