Astrocyte GGTI-mediated Rac1 prenylation upregulates NF-κB expression and promotes neuronal apoptosis following hypoxia/ischemia. (April 2016)

• Record Type: Journal Article
• Authors: Gao, Shangfeng; Mo, Jianbing; Chen, Long; Wang, Yan; Mao, Xueqiang; Shi, Yi; Zhang, Xianfeng; Yu, Rutong; Zhou, Xiuping
• Is Part Of: Neuropharmacology. Volume 103(2016)
• Page Start: 44
• Page End: 56
• Publication Date: 2016-04
• Subjects: Geranylgeranyltransferase I -- Rac1 -- NF-κB -- Brain ischemia -- Stroke -- Apoptosis; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.12.002
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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-κB expression and promoted the neuronal apoptosis after oxygen–glucose deprivation followed by oxygen–glucose regeneration (OGD/R). We found that GGTIβ (a specific subunit of GGTI) and NF-κB-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 GGTIβ 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 Rac1, up-regulated the p65 protein levels and promoted the co-cultured neuronal apoptosis. Furthermore, over-expression of unprenylated Rac1 in astrocytes significantly decreased the neuronal apoptosis. In addition, over-expression of NF-κB-p65 in astrocytes significantly increased the co-cultured neuronal apoptosis under OGD/R condition. Our findings suggest that astrocyte GGTI-mediated Rac1 activation contributed to the DND and that GGTI-Rac1-NF-κB signaling may be a potential target for the therapy of ischemic stroke. Highlights: GGTIβ levels increases in reactive astrocytes and correlates with neuronal apoptosis after tMCAO. The increased GGTIβ expression in astrocytes promotes the neuronal apoptosis after OGD/R. Inhibiting GGTI decreases Rac1 activity in astrocytes after OGD/R. Astrocyte GGTI-mediated Rac1 activation promotes neuronal apoptosis induced by OGD/R. Astrocyte GGTI-mediated Rac1 prenylation upregulates NF-κB expression.