title: Astrocyte GGTI-mediated Rac1 prenylation upregulates NF-κB expression and promotes neuronal apoptosis following hypoxia/ischemia.
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.
authors.affiliation: Institute of Nervous System Diseases, Xuzhou Medical College, 84 West Huai-Hai Road, Xuzhou 221002, Jiangsu, People's Republic of China; Brain Hospital, Affiliated Hospital of Xuzhou Medical College, 99 West Huai-Hai Road, Xuzhou 221002, Jiangsu, People's Republic of China.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Gao
authors.affiliation: The Graduate School, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou 221004, Jiangsu, People's Republic of China.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Mo
authors.affiliation: The Graduate School, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou 221004, Jiangsu, People's Republic of China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical College, 99 West Huai-Hai Road, Xuzhou 221002, Jiangsu, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Graduate School, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou 221004, Jiangsu, People's Republic of China.
authors.forename: Xueqiang
authors.initials: X
authors.lastname: Mao
authors.affiliation: The Graduate School, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou 221004, Jiangsu, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: The Graduate School, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou 221004, Jiangsu, People's Republic of China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Nervous System Diseases, Xuzhou Medical College, 84 West Huai-Hai Road, Xuzhou 221002, Jiangsu, People's Republic of China; Brain Hospital, Affiliated Hospital of Xuzhou Medical College, 99 West Huai-Hai Road, Xuzhou 221002, Jiangsu, People's Republic of China. Electronic address: yu.rutong@163.com.
authors.forename: Rutong
authors.initials: R
authors.lastname: Yu
authors.affiliation: Institute of Nervous System Diseases, Xuzhou Medical College, 84 West Huai-Hai Road, Xuzhou 221002, Jiangsu, People's Republic of China; Brain Hospital, Affiliated Hospital of Xuzhou Medical College, 99 West Huai-Hai Road, Xuzhou 221002, Jiangsu, People's Republic of China. Electronic address: xpzhou@xzmc.edu.cn.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Zhou
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000201:enzymology*; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D017368:Protein Prenylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: Apoptosis; Brain ischemia; Geranylgeranyltransferase I; NF-κB; Rac1; Stroke