Thymidine phosphorylase gene transfer inhibits vascular smooth muscle cell proliferation by upregulating heme oxygenase-1 and p27KIP1.
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.
Li
Wei
W
Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Tanaka
Kuniyoshi
K
Morioka
Koichi
K
Uesaka
Takahiko
T
Yamada
Narihisa
N
Takamori
Atsushi
A
Handa
Mitsuteru
M
Tanabe
Sawaka
S
Ihaya
Akio
A
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
D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051547:Heme Oxygenase-1; D013939:Thymidine Phosphorylase