Hypoxia-induced iNOS expression in microglia is regulated by the P13-kinase/Akt/mTOR signaling pathway and activation of hypoxia inducible factor-1α
Hypoxia-induced iNOS expression in microglia is regulated by the P13-kinase/Akt/mTOR signaling pathway and activation of hypoxia inducible factor-1α
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DOI：
10.1016/j.bcp.2006.06.038
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发表时间：
2006-10-16
影响因子：
5.8
通讯作者：
Fu, Wen-Mei
中科院分区：
文献类型：
--
作者：
Lu, Dah-Yuu;Liou, Houng-Chi;Fu, Wen-Mei
暴露于缺氧诱导的小胶质细胞激活和动物研究表明，脑缺血后神经元细胞死亡与小胶质细胞激活相关。因此，激活的小胶质细胞在缺氧条件下产生的毒性炎症介质可能会加剧脑缺血后的神经元损伤。缺氧诱导因子-1 （HIF-1）主要参与细胞对氧-2水平变化的感知和适应，并受多种生理功能的调节。然而，HIF-1在缺氧条件下小胶质细胞活化中的作用尚未明确。在当前的工作中，我们研究了HIF-1 α参与调节缺氧诱导的小胶质细胞诱导NO合成酶（iNOS）过表达的信号通路。将原代大鼠小胶质细胞培养物和已建立的小胶质细胞系BV-2暴露于缺氧环境中，可诱导iNOS的表达，提示缺氧可导致小胶质细胞的炎症激活。iNOS的诱导伴随着NO的产生。此外，这些事件的分子分析表明，iNOS的表达受磷脂酰肌醇3-激酶（pi3 -激酶）/AKT/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路和缺氧诱导因子-1 α (HIF-1 α)的激活调控。因此，在脑缺血时，缺氧不仅可以直接损伤神经元，还可以通过小胶质细胞的激活间接促进神经元损伤。在这项研究中，我们证明了缺氧通过调节HIF-1 α诱导小胶质细胞中iNOS的表达。(c) 2006爱思唯尔公司版权所有。
Exposure to hypoxia induced microglia activation and animal studies have shown that neuronal cell death is correlated with microglial activation following cerebral ischemia. Thus, it is likely that toxic inflammatory mediators produced by activated microglia under hypoxic conditions may exacerbate neuronal injury following cerebral ischemia. The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O-2 level, which is regulated by many physiological functions.However, the role of HIF-1 in microglia activation underhypoxiahas not yet been defined. In the current work, we investigate the signaling pathways of HIF-1 alpha involved in the regulation of hypoxia-induced overexpression of inducible NO synthase (iNOS) in microglia. Exposure of primary rat microglial cultures as well as established microglial cell line BV-2 to hypoxia induced the expression of iNOS, indicating that hypoxia could lead to the inflammatory activation of microglia. iNOS induction was accompanied with NO production. Moreover, the molecular analysis of these events indicated that iNOS expression was regulated by the phosphatidylinositol 3-kinase (PI3-kinase)/AKT/ mammalian target of rapamycin (mTOR) signaling pathway and activation of hypoxia inducible factor-1 alpha (HIF-1 alpha). Thus, during cerebral ischemia, hypoxia may not only directly damage neurons, but also promote neuronal injury indirectly via microglia activation. In this study, we demonstrated that hypoxia induced iNOS expression by regulation of HIF-1 alpha in microglia. (c) 2006 Elsevier Inc. All rights reserved.