Thymidine phosphorylase gene transfer inhibits vascular smooth muscle cell proliferation by upregulating heme oxygenase-1 and p27KIP1
Thymidine phosphorylase gene transfer inhibits vascular smooth muscle cell proliferation by upregulating heme oxygenase-1 and p27KIP1
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DOI：
10.1161/01.atv.0000168914.85107.64
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发表时间：
2005-07-01
影响因子：
8.7
通讯作者：
Ihaya, A
中科院分区：
文献类型：
--
作者：
Li, W;Tanaka, K;Ihaya, A
目的胸苷磷酸化酶(TP)可促进血管内皮细胞迁移并诱导HO-1的表达。然而，其对血管平滑肌细胞(VSMCs)的影响却知之甚少。方法与结果：将编码人TP基因的噬菌体载体导入大鼠VSMCs，筛选出一株高效表达TP的克隆(C2)。在基础、血清刺激和低氧条件下，C2的迁移和增殖速度慢于空载体(PC)克隆的VSMCs。这种增殖减少与TP诱导的HO-1表达有关，并被TP或HO活性的抑制剂逆转。此外，在C2中，细胞周期蛋白依赖的激酶抑制物(p27(KIP1))比PC中更丰富，细胞周期被阻止在G1期。TP或HO活性抑制剂将C2中p27(KIP1)的表达降低到PC的水平。结论TP过表达可上调血管内皮细胞HO-1的表达，进而增加p27(KIP1)的表达，从而抑制VSMC的迁移和增殖。茶多酚是治疗血管阻塞性疾病的一个有前途的靶点。
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.