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Angiotensin II Induces Inflammatory Response Partly Via Toll-Like Receptor 4-Dependent Signaling Pathway in Vascular Smooth Muscle Cells

机译:血管紧张素II诱导炎症反应部分通过血管平滑肌细胞中的Toll样受体4依赖性信号通路。

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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.
机译:血管紧张素(Ang II)通过促炎作用在动脉粥样硬化中起重要作用。 Toll样受体4(TLR4)可能介导炎症反应。尚不清楚TLR4是否介导Ang II的促炎作用。因此,我们观察到TLR4在Ang II诱导的大鼠血管平滑肌细胞(VSMC)炎症中的作用和信号传导途径。血管紧张素II和LPS刺激大鼠VSMC中TNF-α分泌并抑制6-酮-PGF(1 alpha)产生,上调MMP-9和下调PPARγ和PPARα。 Ang II还明显上调了细胞中TLR4的表达。在Ang II刺激之前用抗TLR4抗体对细胞进行预处理可显着降低Ang II的作用。这些提示Ang II通过TLR4依赖性机制通过调节促炎和抗炎因子刺激VSMC产生炎症。进一步的研究表明,AT1受体拮抗剂洛沙坦或ERK1 / 2抑制剂PD098059抑制Ang II诱导的TLR4表达,TLR4抑制剂阻止Ang II诱导的IP-10表达,抗IP-10抗体部分消除了Ang II诱导的PKC增加,和PKC抑制剂白屈菜红碱抑制Ang II诱导的NF-κB表达。这些证明AngII在VSMC中的TLR4介导的促炎作用涉及AT1 / ERK1 / 2 / TLR4 / IP-10 / PKC /NF-κB途径。我们的结果提供了证据,即Ang II可以部分通过VSMC中的TLR4依赖性信号通路诱导参与动脉粥样硬化发病机制的炎症反应。

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