Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: Involvement of multiple mechanisms
Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: Involvement of multiple mechanisms
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DOI：
10.1161/01.atv.0000105053.46994.5b
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发表时间：
2004-01-01
影响因子：
8.7
通讯作者：
Shimokawa, H
中科院分区：
文献类型：
--
作者：
Matsumoto, Y;Uwatoku, T;Shimokawa, H
我们最近证实Rho激酶，一种小GTdR Rho的效应物，实质上参与动脉硬化的发病机制。在这项研究中，我们研究了Rho激酶是否也参与支架内再狭窄，如果是这样，什么机制involved.Methods和Results-Pigs进行支架植入术在左冠状动脉与或不与管理法舒地尔（30毫克/公斤，每天口服），一个特定的Rho激酶抑制剂，开始2天前的程序持续4周。在第28天，在支架部位观察到与巨噬细胞积聚、胶原沉积和转化生长因子（TGF）-β 1表达相关的冠状动脉直径和新生内膜形成减少，并且所有这些都被法舒地尔显著抑制。在第7天，法舒地尔显着增加TUNEL阳性凋亡细胞的频率，而它倾向于减少新生内膜中溴脱氧尿苷阳性增殖细胞。第7天的蛋白质印迹分析表明ezrin/radixin/moesin家族的磷酸化（体内Rho激酶活性的标志物）和单核细胞趋化蛋白-1和bcl-2的蛋白表达在支架部位上调，并被法舒地尔显著抑制。结论-这些结果表明，长期抑制Rho激酶通过多种机制抑制支架内新生内膜形成，包括减少的血管炎症、增强的细胞凋亡和减少的胶原沉积。
Objective-We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved.Methods and Results-Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg per day orally), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. On day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-beta1 expression were noted at the stent site, and all were significantly suppressed by fasudil. On day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis on day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-1and bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil.Conclusions-These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.