Astrocyte GGTI-mediated Rac1 prenylation upregulates NF-κB expression and promotes neuronal apoptosis following hypoxia/ischemia
Astrocyte GGTI-mediated Rac1 prenylation upregulates NF-κB expression and promotes neuronal apoptosis following hypoxia/ischemia
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星形胶质细胞 GGTI 介导的 Rac1 异戊二烯化上调 NF-κ B 表达并促进缺氧/缺血后神经元凋亡
DOI：
10.1016/j.neuropharm.2015.12.002
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发表时间：
2016-04-01
影响因子：
4.7
通讯作者：
Zhou, Xiuping
中科院分区：
文献类型：
--
作者：
Gao, Shangfeng;Mo, Jianbing;Zhou, Xiuping
中风是美国人的第五大死因，约87%的中风是缺血性中风。星形胶质细胞增生症在缺血性卒中后迟发性神经元死亡(DND)的病理生理学中起重要作用。本文报道了星形胶质细胞香叶基香叶素转移酶I(GGTI)介导的rac1激活上调了核因子-kappaB的表达，促进了缺氧缺糖后神经元的凋亡(OGD/R)。我们发现在短暂性大脑中动脉闭塞(TMCAO)和细胞OGD/R模型中，GGTIβ(GGTI的特异亚单位)和NF-kappa B-p65水平在短暂性大脑中动脉闭塞(TMCAO)和细胞OGD/R模型的反应性星形胶质细胞中均显著上调。GGTIβ和P65的表达增加与缺血区的DND有关。用其特异性抑制剂GGTI-2147抑制星形胶质细胞GGTI活性，可降低GGTI底物rac1的活性，下调p65的表达，改善OGD/R诱导的神经细胞凋亡。转染野生型rac1的星形胶质细胞可上调p65蛋白水平，促进共培养神经元的凋亡。此外，星形胶质细胞中未戊烯基化的RACL的过度表达显著减少了神经元的凋亡。此外，在OGD/R条件下，星形胶质细胞中过表达的核因子-kappaB-p65显著增加了共同培养的神经元的凋亡率。我们的研究结果提示，星形胶质细胞GGTI介导的racl激活参与了DND的发生，GGTI-rac1-NF-kappa B信号通路可能成为治疗缺血性卒中的潜在靶点。(C)2015爱思唯尔有限公司。保留所有权利。
Stroke is the fifth leading cause of death for Americans, and about 87% of all strokes are ischemic strokes. Astrogliosis plays a crucial role in the pathophysiology of delayed neuronal death (DND) following ischemic stroke. Here we reported that astrocyte geranylgeranyltransferase I (GGTI)-mediated Rac1 activation up-regulated NF-kappa B expression and promoted the neuronal apoptosis after oxygen glucose deprivation followed by oxygen glucose regeneration (OGD/R). We found that GGTI beta (a specific subunit of GGTI) and NF-kappa B-p65 levels as determined by Western blot and/or immunofluorescent analysis were significantly up-regulated in the reactive astrocytes both in rat transient middle cerebral artery occlusion (tMCAO) and in cell OGD/R models. The increased expression of GGTI beta and p65 was associated with the DND in the ischemic brain. Inhibiting astrocyte GGTI activity by its specific inhibitor GGTi-2147 treatment reduced the activity of Rac1 (one of substrates for GGTI), down-regulated the expression of p65, and ameliorated the OGD/R-induced neuronal apoptosis. Astrocytes transfected with wild type Rac1, but not the unprenylated Racl, up-regulated the p65 protein levels and promoted the co-cultured neuronal apoptosis. Furthermore, over-expression of unprenylated Racl in astrocytes significantly decreased the neuronal apoptosis. In addition, over-expression of NF-kappa B-p65 in astrocytes significantly increased the co-cultured neuronal apoptosis under OGD/R condition. Our findings suggest that astrocyte GGTI-mediated Racl activation contributed to the DND and that GGTI-Rac1-NF-kappa B signaling may be a potential target for the therapy of ischemic stroke. (C) 2015 Elsevier Ltd. All rights reserved.