Suppressing inflammation by inhibiting the NF-κB pathway contributes to the neuroprotective effect of angiotensin-(1-7) in rats with permanent cerebral ischaemia
Suppressing inflammation by inhibiting the NF-κB pathway contributes to the neuroprotective effect of angiotensin-(1-7) in rats with permanent cerebral ischaemia
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DOI：
10.1111/j.1476-5381.2012.02105.x
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发表时间：
2012-12-01
影响因子：
7.3
通讯作者：
Zhang, Yingdong
中科院分区：
文献类型：
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作者：
Jiang, Teng;Gao, Li;Zhang, Yingdong
血管紧张素-（1-7）[Ang-（1-7）]在外周器官具有抗炎作用，但其在缺血性卒中中的作用尚不清楚。我们在永久性大脑中动脉闭塞（permanent middle cerebral artery occlusion，pMCAO）大鼠模型中研究了其抗炎作用是否与Ang-（1 - 7）诱导的神经保护作用有关。血管紧张素II 2型受体拮抗剂PD 123319或人工CSF注入雄性Sprague-道利大鼠从pMCAO发作前48 h开始直至处死。pMCAO后24小时，通过评估梗死体积和神经功能缺损来分析Ang-（1-7）的神经保护作用。采用分光光度法检测氧化应激水平。通过Western blot和免疫组化分析评估NF-κ B的活化。通过Western印迹分析检测考克斯-2的水平，通过ELISA检测促炎细胞因子的浓度。显著减少梗死体积和改善神经功能缺损。它降低了氧化应激水平，抑制NF-κ B活性，同时减少了梗死周围区域的促炎细胞因子和考克斯-2。Ang-（1-7）的这些作用被A-779逆转，但不被PD 123319逆转。此外，单独注射A-779可增加pMCAO大鼠的氧化应激水平，增强NF-κ B活性，并上调促炎细胞因子和考克斯-2的表达。结论与意义Ang-（1-7）可能通过抑制Mas受体介导的NF-κ B依赖性通路发挥抗炎作用。
BACKGROUND AND PURPOSEAngiotensin-(1-7) [Ang-(1-7)] has anti-inflammatory effects in peripheral organs, but its effects in ischaemic stroke are unclear as yet. We investigated whether its anti-inflammatory effect contributes to the neuroprotection induced by Ang-(1-7) in a rat model of permanent middle cerebral artery occlusion (pMCAO).EXPERIMENTAL APPROACHWe infused Ang-(1-7), Mas receptor antagonist A-779, angiotensin II type 2 receptor antagonist PD123319 or artificial CSF into the right lateral ventricle of male Sprague-Dawley rats from 48 h before onset of pMCAO until the rats were killed. Twenty-four hours after pMCAO, the neuroprotective effect of Ang-(1-7) was analysed by evaluating infarct volume and neurological deficits. The levels of oxidative stress were detected by spectrophotometric assay. The activation of NF-kappa B was assessed by Western blot and immunohistochemistry analysis. The level of COX-2 was tested by Western blot analysis and concentrations of pro-inflammatory cytokines were measured by elisa.KEY RESULTSInfusion of Ang-(1-7), i.c.v., significantly reduced infarct volume and improved neurological deficits. It decreased the levels of oxidative stress and suppressed NF-kappa B activity, which was accompanied by a reduction of pro-inflammatory cytokines and COX-2 in the peri-infarct regions. These effects of Ang-(1-7) were reversed by A-779 but not by PD123319. Additionally, infusion of A-779 alone increased oxidative stress levels and enhanced NF-kappa B activity, which was accompanied by an up-regulation of pro-inflammatory cytokines and COX-2.CONCLUSION AND IMPLICATIONSOur findings indicate that suppressing NF-kappa B dependent pathway via Mas receptor may represent one mechanism that contributes to the anti-inflammatory effects of Ang-(1-7) in rats with pMCAO.