PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway
PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway
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DOI：
10.1038/labinvest.2009.45
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发表时间：
2009-08-01
影响因子：
5
通讯作者：
Gou, Wei
中科院分区：
文献类型：
--
作者：
Ji, Yuanyuan;Liu, Juntian;Gou, Wei
动脉粥样硬化日益被认为是一种慢性炎症性疾病。血管紧张素II（Ang II）是炎症反应中的一个关键因素，从而促进动脉粥样硬化的发病机制。Toll样受体4（TLR4）激活信号通路，导致与动脉粥样硬化病因相关的促炎细胞因子表达。过氧化物酶体增殖物激活受体γ（PPARγ）激动剂被认为在调节血管炎症和动脉粥样硬化方面具有重要作用。在此，我们在体内和体外研究了罗格列酮对Ang II介导的炎症反应的调节作用。我们还检测了TLR4依赖的信号通路是否参与罗格列酮对血管平滑肌细胞（VSMCs）中Ang II诱导的促炎反应的抑制作用。雄性Sprague - Dawley大鼠通过皮下输注Ang II和/或口服罗格列酮，持续7天。罗格列酮减轻了Ang II输注大鼠的收缩压升高。罗格列酮还减少了Ang II诱导的促炎介质（TLR4、基质金属蛋白酶 - 9和肿瘤坏死因子 - α）的产生，但在体内和体外都增强了抗炎介质（PPARγ和6 - 酮 - PGF(1α)）的产生。此外，用TLR4抑制剂和TLR4小干扰RNA（siRNA）处理VSMCs表明，罗格列酮对VSMCs中Ang II介导的炎症反应的调节作用与TLR4有关。用罗格列酮处理细胞对Ang II受体表达（AT1和AT2）影响较小，但下调了AT1依赖的ERK1/2激活。然后，用TLR4 siRNA、干扰素 - γ诱导蛋白10（IP - 10）siRNA以及特异性蛋白激酶C（PKC）抑制剂处理VSMCs进一步揭示，信号通路（TLR4/IP - 10/PKC/NF - κB）参与了罗格列酮对VSMCs中Ang II诱导的促炎反应的抑制作用。总之，TLR4可能是参与PPARγ激动剂罗格列酮对VSMCs中Ang II介导的炎症反应改善作用的一个药物靶点。此外，罗格列酮通过干扰TLR4依赖的信号通路（ERK1/2/TLR4/IP - 10/PKC/NF - κB）发挥其抗炎作用，以预防和治疗动脉粥样硬化疾病。《实验研究》（2009年）89卷，887 - 902页；doi:10.1038/labinvest.2009.45；2009年5月18日在线发表
Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Angiotensin II (Ang II) is a critical factor in inflammatory responses, so as to promote the pathogenesis of atherosclerosis. Toll-like receptor 4 (TLR4) activates signaling pathways leading to the expression of pro-inflammatory cytokines implicated in the etiology of atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are considered to be important in modulating vascular inflammation and atherosclerosis. Herein, we investigated the modulatory effects of rosiglitazone on Ang II-mediated inflammatory responses both in vivo and in vitro. We also examined whether TLR4-dependent signaling pathway was involved in the inhibitory effects of rosiglitazone on Ang II-induced pro-inflammatory responses in vascular smooth muscle cells (VSMCs). Male Sprague-Dawley rats received Ang II by subcutaneous infusion and/or rosiglitazone per os for 7 days. Systolic blood pressure rise in Ang II-infused rats was attenuated by rosiglitazone. Rosiglitazone also reduced Ang II-induced generation of pro-inflammatory mediators (TLR4, matrix metalloproteinase-9 and tumor necrosis factor-alpha), but enhanced production of anti-inflammatory mediators (PPAR gamma and 6-keto-PGF(1 alpha)) both in vivo and in vitro. Furthermore, treatment of VSMCs with both the TLR4 inhibitor and TLR4 small-interfering RNA (siRNA) showed that the modulatory effects of rosiglitazone on Ang II-mediated inflammatory responses in VSMCs were related to TLR4. Treatment of the cells with rosiglitazone had little effect on Ang II receptors expression (AT1 and AT2), but downregulated AT1-dependent ERK1/2 activation. Then, treatment of VSMCs with TLR4 siRNA, interferon-gamma-inducible protein 10 (IP-10) siRNA and with the special protein kinase C (PKC) inhibitor further revealed that the signaling pathway (TLR4/IP-10/PKC/NF-kappa B) was involved in the inhibitory effects of rosiglitazone on Ang II-induced pro-inflammatory responses in VSMCs. In conclusion, TLR4 may be a drug target involved in the ameliorative effects of PPAR gamma agonist, rosiglitazone, on Ang II-mediated inflammatory responses in VSMCs. Moreover, rosiglitazone exerts its anti-inflammatory effect by interfering with the TLR4-dependent signaling pathway (ERK1/2/TLR4/IP-10/PKC/NF-kappa B) to prevent and treat atherosclerotic diseases. Laboratory Investigation (2009) 89, 887-902; doi:10.1038/labinvest.2009.45; published online 18 May 2009