Angiotensin induces inflammatory activation of human vascular smooth muscle cells
Angiotensin induces inflammatory activation of human vascular smooth muscle cells
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DOI：
10.1161/01.atv.19.7.1623
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发表时间：
1999-07-01
影响因子：
8.7
通讯作者：
Kübler, W
中科院分区：
文献类型：
--
作者：
Kranzhöfer, R;Schmidt, J;Kübler, W
多种数据表明，肾素-血管紧张素系统有助于动脉粥样硬化的发病机制。血管紧张素系统的致动脉粥样硬化作用只能部分地通过其效应物血管紧张素II对血压、平滑肌细胞（SMC）生长或抗纤溶活性的影响来解释。由于血管壁的慢性炎症是动脉粥样硬化的标志，我们假设血管紧张素II可能引起血管平滑肌细胞的炎症信号。用血管紧张素刺激人血管平滑肌细胞。通过测定白细胞介素-6（IL-6）释放到培养基中、通过RT-PCR检测IL-6 mRNA以及在电泳迁移率变动试验中证明核因子-κ B活化来评估炎症活化。血管紧张素II浓度依赖性（1 nmol/L至1 μ mol/L）通过激活血管紧张素II 1型受体（通过受体拮抗剂氯沙坦的抑制作用证明）刺激SMC产生IL-6。血管紧张素I也增加SMC产生IL-6。这种作用被抑制由卡托普利和雷米普利拉，提示血管紧张素转换酶在平滑肌细胞中的血管紧张素I血管紧张素II的转换。IL-6的稳态mRNA在血管紧张素II刺激后增加，表明在翻译前水平调节血管紧张素诱导的IL-6释放。此外，促炎性转录因子核因子-κ B，这是大多数细胞因子基因转录所必需的，也被血管紧张素II激活。吡咯烷二硫代氨基甲酸酯抑制血管紧张素II诱导的IL-6释放，这一发现与活性氧作为第二信使参与血管紧张素介导的细胞因子产生相一致。这些数据证明了血管紧张素通过刺激细胞因子的产生和核因子-κ B的活化在人血管SMC中引起炎症反应的能力。血管壁的炎症激活由失调的肾素-血管紧张素系统可能有助于动脉粥样硬化的发病机制。
Multiple data suggest that the renin-angiotensin system contributes to the pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin system can only in part be explained by the influence of its effector angiotensin II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic activity. Because chronic inflammation of the vessel wall is a hallmark of atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin. Inflammatory activation was assessed by determination of interleukin-6 (IL-6) release into the culture medium, detection of IL-6 mRNA by RT-PCR, and demonstration of activation of nuclear factor-kappa B in electrophoretic mobility shift assays. Angiotensin II concentration-dependently (1 nmol/L to 1 mu mol/L) stimulated IL-6 production by SMCs via activation of the angiotensin II type 1 receptor (demonstrated by the inhibitory action of the receptor antagonist losartan). Angiotensin I increased IL-6 production by SMCs, too. This effect was inhibited by captopril and ramiprilat, suggesting conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme in SMCs. Steady-state mRNA for IL-6 was augmented after stimulation with angiotensin II, suggesting regulation of angiotensin-induced IL-6 release at the pretranslational level. Moreover, the proinflammatory transcription factor nuclear factor-kappa B, which is necessary for transcription of most cytokine genes, was also activated by angiotensin II. Pyrrolidine dithiocarbamate suppressed angiotensin II-induced IL-6 release, a finding compatible with involvement of reactive oxygen species as second messengers in cytokine production mediated by angiotensin. The data demonstrate the ability of angiotensin to elicit an inflammatory response in human vascular SMCs by stimulation of cytokine production and activation of nuclear factor-kappa B. Inflammatory activation of the vessel wall by a dysregulated renin-angiotensin system may contribute to the pathogenesis of atherosclerosis.