Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury
Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury
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DOI：
10.1016/j.bbrc.2006.05.056
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发表时间：
2006-07-14
影响因子：
3.1
通讯作者：
Kubota, I
中科院分区：
文献类型：
--
作者：
Shishido, T;Nozaki, N;Kubota, I
背景：现已证实，血管损伤后的炎症对血管成形术、支架置入术和搭桥术等血管重建术后的再狭窄有显著影响。然而，调控血管损伤后炎症和修复的机制还不完全清楚。在此，我们报道了血管损伤介导的细胞因子的表达、活性氧物种(ROS)的产生以及随后的新生内膜形成需要Toll样受体-2(TLR-2)介导的在体信号通路。方法和结果：在非转基因胎鼠(NLC)和TLR-2基因敲除(TLR-2KO)小鼠股动脉周围放置袖带诱导血管损伤。NLC小鼠放置袖带后，TLR-2在中层和外膜的表达均显著增加。有趣的是，我们发现TLR-2KO小鼠与NLC小鼠相比，肿瘤坏死因子-α、白介素1-β(IL-1β)、IL-6和单核细胞趋化蛋白-1等炎症基因的表达显著降低。此外，与NLC小鼠相比，TLR-2KO小鼠血管损伤后ROS的产生减少。由于我们观察到内源性TLR-2激活在调节血管损伤后炎症反应和ROS产生中的重要作用，我们确定抑制内源性TLR-2激活是否可以抑制血管损伤后新生内膜的增殖。在血管损伤后2周和4周，TLR-2KO小鼠较WT小鼠明显抑制新生内膜的增殖。结论：内源性TLR-2的激活可能在血管炎症及随后的损伤血管新生内膜形成的调节中起中心作用。(C)2006 Elsevier Inc.保留所有权利。
Background: It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo.Methods and results: Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-alpha, interleukin-1 beta (IL-1 beta), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury.Conclusions: These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels. (c) 2006 Elsevier Inc. All rights reserved.