Angiotensin II Induces Inflammatory Response Partly Via Toll-Like Receptor 4-Dependent Signaling Pathway in Vascular Smooth Muscle Cells
Angiotensin II Induces Inflammatory Response Partly Via Toll-Like Receptor 4-Dependent Signaling Pathway in Vascular Smooth Muscle Cells
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DOI：
10.1159/000218173
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发表时间：
2009-01-01
影响因子：
--
通讯作者：
Liu, Na
中科院分区：
文献类型：
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作者：
Ji, Yuanyuan;Liu, Juntian;Liu, Na
血管紧张素(Ang II)通过促炎作用在动脉粥样硬化中发挥重要作用。Toll样受体4(TLR4)可能介导炎症反应。目前尚不清楚TLR4是否介导了Ang II的促炎作用。因此，我们观察了TLR4在Ang II诱导的大鼠血管平滑肌细胞(VSMCs)炎症中的作用及其信号转导途径。Ang II和LPS刺激大鼠VSMCs分泌TNF-α，抑制6-keto-PGF(1α)的产生，上调MMP9，下调PPAR-γ和PPARα的表达。Ang II还可明显上调TLR4在细胞中的表达。Ang II刺激细胞前用抗TLR4抗体可明显减弱Ang II的作用。提示Ang II通过TLR4依赖的机制调节促炎症和抗炎因子，从而刺激VSMC产生炎症。进一步的研究表明，AT1受体拮抗剂氯沙坦或ERK1/2抑制剂PD098059抑制Ang II诱导的TLR4表达，TLR4抑制剂抑制Ang II诱导的IP-10表达，抗IP-10抗体部分阻断Ang II诱导的PKC增加，PKC抑制剂白屈菜红碱抑制Ang II诱导的NF-kappaB表达。提示TLR4介导的Ang II促VSMC炎症反应涉及AT1/ERK1/2/TLR4/IP-10/PKC/NF-kappa B通路。我们的结果为Ang II诱导炎症反应参与动脉粥样硬化的发病机制提供了证据，部分是通过TLR4依赖的VSMCs信号通路实现的。版权所有(C)2009 S.Karger AG，巴塞尔
Angiotensin (Ang II) plays an important role in atherosclerosis through proinflammatory effect. Toll-like receptor 4 (TLR4) may mediate inflammatory response. It is unknown whether TLR4 mediates the proinflammatory effect of Ang II. Thus, we observed the role and signaling pathway of TLR4 in Ang II-induced inflammation in rat vascular smooth muscle cells (VSMCs). Ang II and LPS stimulated TNF-alpha secretion and inhibited 6-keto-PGF(1 alpha) production, upregulated MMP-9 and downregulated PPAR gamma and PPAR alpha in rat VSMCs. Ang II also distinctly upregulated TLR4 expression in the cells. Pretreatment of the cells with anti-TLR4 antibody prior to Ang II stimulation significantly diminished the effects of Ang II. These suggest that Ang II stimulates VSMCs to produce inflammation through regulation of the proinflammatory and the antiinflammtory factors via TLR4-dependent mechanism. The further investigations showed that AT1 receptor antagonist losartan or ERK1/2 inhibitor PD098059 inhibited Ang II-induced TLR4 expression, TLR4 inhibitor prevented Ang II-induced IP-10 expression, anti-IP-10 antibody partly abolished Ang II-induced PKC increase, and PKC inhibitor chelerythrine suppressed Ang II-induced NF-kappa B expression. These demonstrate that TLR4-mediated proinflammatory effect of Ang II in VSMCs involves AT1/ERK1/2/TLR4/IP-10/PKC/NF-kappa B pathway. Our results provide the evidence that Ang II induces inflammatory response involved in pathogenesis of atherosclerosis partly via TLR4-dependent signaling pathway in VSMCs. Copyright (C) 2009 S. Karger AG, Basel