title: Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling.
abstract: BACKGROUND
  Celecoxib has been shown to have antitumor effects that may be mediated through the cyclooxygenase-independent inhibition of Akt signaling. Here, we examined the effects of celecoxib on neointimal formation after balloon injury and its mechanism of action.
  
  
  RESULTS
  In vitro experiments were performed to evaluate the effects of celecoxib on the Akt/GSK signaling axis and the viability of rat vascular smooth muscle cells (VSMCs). In vivo experiments examined the effects of celecoxib, aspirin, and vehicle on neointimal growth after denudation injury to rat carotid arteries. In vitro, celecoxib suppressed the phosphorylation of Akt and GSK in cultured VSMCs, leading to a reduction in viable cell number, which was reversed by transduction of constitutively active Akt. Such a reduction in cell number was mediated by inhibition of proliferation and induction of apoptosis. In vivo, celecoxib reduced injury-induced phosphorylation of Akt and GSK, reduced VSMC proliferation, and increased caspase-3 activation and VSMC apoptosis at 3 days after injury, whereas aspirin had no effect. At 2 weeks after injury, celecoxib reduced intima-to-media ratio, whereas aspirin had no effect. Adenovirus-mediated delivery of dominant negative Akt was as effective as celecoxib at inhibiting neointimal formation. Conversely, gene delivery of constitutively active Akt significantly reversed the inhibition of intimal hyperplasia by celecoxib, providing causal evidence that the modulation of Akt signaling by celecoxib is a physiologically relevant mechanism.
  
  
  CONCLUSIONS
  Celecoxib is a potential inhibitor of neointimal formation by blocking injury-induced Akt activation. These findings suggest a potential use for celecoxib in the prevention of restenosis after angioplasty.
authors.affiliation: Cardiovascular Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Yang
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Kyung-Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: You
authors.forename: Soo-In
authors.initials: SI
authors.lastname: Jeon
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Myoung-Mook
authors.initials: MM
authors.lastname: Lee
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000818:Animals; D017209:Apoptosis; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006965:Hyperplasia; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib