NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin-induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes.
NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin-induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes.
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DOI：
10.1186/1478-811x-10-35
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发表时间：
2012-11-23
期刊：
影响因子：
--
通讯作者：
Yang CM
中科院分区：
文献类型：
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作者：
Lin CC;Hsieh HL;Shih RH;Chi PL;Cheng SE;Chen JC;Yang CM
基质金属蛋白酶-9 （Matrix metalloproteinase-9, MMP-9）在脑炎症、损伤和神经退行性变的病理过程中起重要作用。此外，缓激素（BK）可诱导脑星形胶质细胞中几种炎症蛋白的表达。最近的研究表明，氧化应激的增加与大脑炎症和损伤有关。然而，BK是否通过氧化应激介导MMP-9的表达仍然是未知的。本研究研究了氧化还原信号在bk诱导的大鼠脑星形胶质细胞（RBA-1细胞）中MMP-9表达中的作用。在这项研究中，我们首先证明了活性氧（ROS）在体外培养的脑星形胶质细胞和动物脑组织（体内）模型中对bk诱导的MMP-9表达起着至关重要的作用。接下来，bk诱导的MMP-9表达通过Ca2+介导的PKC-α连接p47phox/NADPH氧化酶2 (Nox2)/ROS信号通路介导。nox2依赖性ROS的产生导致下游转录因子AP-1（即c-Fos和c-Jun）的激活和上调，AP-1与MMP-9启动子区结合，从而开启MMP-9基因的转录。在功能上，bk诱导的MMP-9表达增强了星形细胞的迁移。这些结果表明，在RBA-1细胞中，PKC-α-介导的Nox2/ROS信号激活AP-1 （c-Fos/c-Jun）是上调MMP-9和BK增强细胞迁移的必要条件。
Matrix metalloproteinase-9 (MMP-9) plays a crucial role in pathological processes of brain inflammation, injury, and neurodegeneration. Moreover, bradykinin (BK) induces the expression of several inflammatory proteins in brain astrocytes. Recent studies have suggested that increased oxidative stress is implicated in the brain inflammation and injury. However, whether BK induced MMP-9 expression mediated through oxidative stress remains virtually unknown. Herein we investigated the role of redox signals in BK-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells). In the study, we first demonstrated that reactive oxygen species (ROS) plays a crucial role in BK-induced MMP-9 expression in cultured brain astrocytes (in vitro) and animal brain tissue (in vivo) models. Next, BK-induced MMP-9 expression is mediated through a Ca2+-mediated PKC-α linking to p47phox/NADPH oxidase 2 (Nox2)/ROS signaling pathway. Nox2-dependent ROS generation led to activation and up-regulation of the downstream transcriptional factor AP-1 (i.e. c-Fos and c-Jun), which bound to MMP-9 promoter region, and thereby turned on transcription of MMP-9 gene. Functionally, BK-induced MMP-9 expression enhanced astrocytic migration. These results demonstrated that in RBA-1 cells, activation of AP-1 (c-Fos/c-Jun) by the PKC-α-mediated Nox2/ROS signals is essential for up-regulation of MMP-9 and cell migration enhanced by BK.