Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulated kinase expression and activation
Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulated kinase expression and activation
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DOI：
10.1016/j.atherosclerosis.2014.06.011
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发表时间：
2014-09-01
期刊：
影响因子：
5.3
通讯作者：
Golledge, Jonathan
中科院分区：
文献类型：
--
作者：
Clancy, Paula;Koblar, Simon A.;Golledge, Jonathan
背景资料：目的：探讨细胞外信号调节激酶（ERK）1/2在血管紧张素II（AII）1型受体（ATR 1）阻断剂（ARB）诱导的人颈动脉粥样硬化（AS）炎症反应中的作用。从接受颈动脉内膜切除术的患者获得的动脉粥样硬化样品在有和没有ATR 1的情况下培养（厄贝沙坦）、ERK 1/2（PD 98059）、AII（[ Sar（1），Ile（8）]-AII）和血管紧张素转换酶（ACE）2（DX 600）阻断。还研究了ATR 1和ERK 1/2阻断和外源性AII对血清刺激的健康原代血管细胞的体外作用。结果通过使用ELISA测量细胞因子（白细胞介素（IL）-6、IL-8、C-C基序趋化因子（CCL）2、C-X-C基序趋化因子（CXCL）5、骨保护素（OPG）、骨桥蛋白（OPN）、CXCL 16）、上清液中的浓度和组织裂解物中的磷酸化ERK 1/2来评估。结果：Irbesartan可降低动脉粥样硬化组织和原代血管细胞培养上清中IL-6、IL-8、CCL 2、CXCL 5、OPG、OPN和CXCL 16的浓度。动脉粥样硬化上清液中细胞因子水平的降低与组织中ERK 1/2表达的降低相关。抑制ERK 1/2下调了动脉粥样硬化和细胞培养上清液中的IL-6、IL-8和CXCL 5。AII和ACE 2封锁没有影响细胞因子或活性ERK 1/2的水平在atheroma culture.Conclusion：我们的研究结果表明，ATR 1封锁下调动脉粥样硬化组织ERK 1/2的表达，导致细胞因子的产生减少，非AII激动剂ATR 1信号转导反应可能会诱导这些炎症相关的细胞因子在动脉粥样硬化的表达。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Background: A number of studies have suggested that angiotensin II (AII) receptor type 1 (ATR1) blocking drugs (ARBs) have anti-inflammatory effects however the mechanisms responsible are poorly investigated.Objective: To determine the role of extracellular signal regulated kinase (ERK)1/2 in ARB induced anti-inflammatory effects within human carotid atherosclerosis.Methods: Atheroma samples obtained from patients undergoing carotid endarterectomy were cultured with and without ATR1 (irbesartan), ERK1/2 (PD98059), AII ([ Sar(1), Ile(8)]-AII) and angiotensin converting enzyme (ACE) 2 (DX600) blockade. The in vitro effects of ATR1 and ERK1/2 blockade and exogenous AII on serum stimulated healthy, primary vascular cells were also investigated. Outcome was assessed by measuring cytokine, (interleukin (IL)-6, IL-8, C-C motif chemokine (CCL) 2, C-X-C motif chemokine (CXCL) 5, osteoprotegerin (OPG), osteopontin (OPN), CXCL16), concentrations in supernatants and phosphorylated ERK1/2 in the tissue lysates using ELISA. ERK1/2 expression in the tissue was assessed using Western blotting.Results: Irbesartan reduced concentrations of IL-6, IL-8, CCL2, CXCL5, OPG, OPN and CXCL16 in both atheroma and primary vascular cell culture supernatants. The reduction in cytokine levels in the atheroma supernatant was correlated to a reduction in ERK1/2 expression in the tissue. Inhibition of ERK1/2 downregulated IL-6, IL-8 and CXCL5 in both atheroma and cell culture supernatants. AII and ACE2 blockade had no impact on cytokine or active ERK1/2 levels in the atheroma culture.Conclusion: Our findings suggest that ATR1 blockade downregulates atheroma tissue ERK1/2 expression leading to a reduction in cytokine production and that a non-AII agonist ATR1 signalling response may induce expression of these inflammation associated cytokines in the atheroma. (C) 2014 Elsevier Ireland Ltd. All rights reserved.