title: Thymidine phosphorylase gene transfer inhibits vascular smooth muscle cell proliferation by upregulating heme oxygenase-1 and p27KIP1.
abstract: OBJECTIVE
  Thymidine phosphorylase (TP) reportedly promotes endothelial cell migration and induces heme oxygenase (HO)-1 expression. However, its effect on vascular smooth muscle cells (VSMCs) is poorly understood. In this study, we examined the effect of TP on VSMCs in vitro and in vivo.
  
  
  RESULTS
  Phagemid vector encoding human TP gene was transfected into rat VSMCs, and a clone overexpressing TP was selected (C2). C2 showed a slower migration and proliferation than VSMCs cloned with empty vector (pC) under basal, serum-stimulated, and hypoxic conditions. This decrease in proliferation correlated with TP-induced HO-1 expression and was reversed by inhibitors of either TP or HO activity. Furthermore, in C2, the cyclin-dependent kinase inhibitor (p27KIP1) was much more abundant than in pC, and the cell cycle was arrested at the G1 phase. TP or HO activity inhibitors decreased p27(KIP1) expression in C2 to the level seen in pC. Adventitial TP gene delivery significantly reduced neointimal VSMC migration and neointima formation in balloon-injured rat carotid arteries.
  
  
  CONCLUSIONS
  TP overexpression upregulated HO-1 expression and consequently increased p27(KIP1) in cultured VSMCs, and inhibited VSMC migration and proliferation in vitro and in vivo. TP represents a promising target for treating vascular obstructive disease.
authors.affiliation: Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Morioka
authors.forename: Takahiko
authors.initials: T
authors.lastname: Uesaka
authors.forename: Narihisa
authors.initials: N
authors.lastname: Yamada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takamori
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Handa
authors.forename: Sawaka
authors.initials: S
authors.lastname: Tanabe
authors.forename: Akio
authors.initials: A
authors.lastname: Ihaya
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology*; D016893:Carotid Stenosis / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004790:Enzyme Induction; D018014:Gene Transfer Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013939:Thymidine Phosphorylase / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051547:Heme Oxygenase-1; D013939:Thymidine Phosphorylase