Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury.
Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury.
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DOI：
10.1186/1742-2094-9-48
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发表时间：
2012-03-07
影响因子：
9.3
通讯作者：
Cano E
中科院分区：
文献类型：
--
作者：
Sobrado M;Ramirez BG;Neria F;Lizasoain I;Arbones ML;Minami T;Redondo JM;Moro MA;Cano E
细胞内钙浓度[Ca2+]i的增加是脑缺血后发生的第一个事件之一。一个关键的[Ca2+]i调节信号分子是磷酸酶钙调磷酸酶（CN），它在炎症级联反应的调节中起重要作用。在此，我们分析了内源性cn1调节因子（Rcan1）在大脑中动脉闭塞引起的实验性缺血性脑卒中中的作用。动物进行局灶性脑缺血再灌注。为了评估Rcan1在脑卒中后的作用，我们测量了Rcan1敲除（KO）和野生型（WT）小鼠再灌注48小时后的梗死体积。体外研究是在富含星形胶质细胞的皮层原代培养物中进行的，培养物受到3%氧（缺氧）和葡萄糖剥夺（HGD）的影响。采用腺病毒载体分析Rcan1-4蛋白过表达的影响。免疫组织化学和免疫印迹法检测蛋白表达，实时定量反转录聚合酶链反应（real time qRT-PCR）检测mRNA表达。脑缺血/再灌注（I/R）损伤使钙诱导的Rcan1亚型（Rcan1-4）的mRNA和蛋白表达增加。I/ r诱导的Rcan1蛋白表达主要发生在星形胶质细胞中，在体外缺血模型中，HGD处理小鼠星形胶质细胞培养物诱导了Rcan1-4 mRNA和蛋白的表达。外源性Rcan1-4过表达抑制炎症标志物环加氧酶2的产生。缺乏Rcan1的小鼠炎症相关基因的表达更高，导致更大的梗死体积。我们的研究结果支持Rcan1在中风炎症反应中的保护作用，并强调了神经胶质隔室在缺血后发生的炎症反应中的重要性。提高对缺血性损伤的非神经元机制的理解有望为急性缺血性卒中的治疗提供新的途径。
An increase in intracellular calcium concentration [Ca2+]i is one of the first events to take place after brain ischemia. A key [Ca2+]i-regulated signaling molecule is the phosphatase calcineurin (CN), which plays important roles in the modulation of inflammatory cascades. Here, we have analyzed the role of endogenous regulator of CN 1 (Rcan1) in response to experimental ischemic stroke induced by middle cerebral artery occlusion. Animals were subjected to focal cerebral ischemia with reperfusion. To assess the role of Rcan1 after stroke, we measured infarct volume after 48 h of reperfusion in Rcan1 knockout (KO) and wild-type (WT) mice. In vitro studies were performed in astrocyte-enriched cortical primary cultures subjected to 3% oxygen (hypoxia) and glucose deprivation (HGD). Adenoviral vectors were used to analyze the effect of overexpression of Rcan1-4 protein. Protein expression was examined by immunohistochemistry and immunoblotting and expression of mRNA by quantitative real-time Reverse-Transcription Polymerase Chain Reaction (real time qRT-PCR). Brain ischemia/reperfusion (I/R) injury in vivo increased mRNA and protein expression of the calcium-inducible Rcan1 isoform (Rcan1-4). I/R-inducible expression of Rcan1 protein occurred mainly in astroglial cells, and in an in vitro model of ischemia, HGD treatment of primary murine astrocyte cultures induced Rcan1-4 mRNA and protein expression. Exogenous Rcan1-4 overexpression inhibited production of the inflammatory marker cyclo-oxygenase 2. Mice lacking Rcan1 had higher expression of inflammation associated genes, resulting in larger infarct volumes. Our results support a protective role for Rcan1 during the inflammatory response to stroke, and underline the importance of the glial compartment in the inflammatory reaction that takes place after ischemia. Improved understanding of non-neuronal mechanisms in ischemic injury promises novel approaches to the treatment of acute ischemic stroke.
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