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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1370.)
© 2005 American Heart Association, Inc.

Vascular Biology

Thymidine Phosphorylase Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation by Upregulating Heme Oxygenase-1 and p27^KIP1

Wei Li; Kuniyoshi Tanaka; Koichi Morioka; Takahiko Uesaka; Narihisa Yamada; Atsushi Takamori; Mitsuteru Handa; Sawaka Tanabe; Akio Ihaya

From the Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Correspondence to Dr Kuniyoshi Tanaka, Professor and Chairman, Second Department of Surgery, Faculty of Medical Sciences, University of Fukui 23-3 Shimoaizuki, Matsuoka-Cho, Yoshida-Gun, Fukui 9101193, Japan. E-mail kunitan{at}fmsrsa.fukui-med.ac.jp

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.

Methods and 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 (p27^KIP1) 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.

Gene transfer of thymidine phosphorylase (TP) into cultured VSMCs significantly decreased their migration and proliferation. Furthermore, adventitial delivery of TP gene to rat balloon-injured carotid artery significantly reduced neointimal VSMC migration and inhibited neointima formation. TP may be useful in treating vascular obstructive disease.

Key Words: angiogenesis • gene therapy • thymidine phosphorylase • vascular obstructive disease • vascular smooth muscle cells