title: A global transcriptomic view of the multifaceted role of glutathione peroxidase-1 in cerebral ischemic-reperfusion injury.
abstract: Transient cerebral ischemia often results in secondary ischemic/reperfusion injury, the pathogenesis of which remains unclear. This study provides a comprehensive, temporal description of the molecular events contributing to neuronal injury after transient cerebral ischemia. Intraluminal middle cerebral artery occlusion (MCAO) was performed to induce a 2-h ischemia with reperfusion. Microarray analysis was then performed on the infarct cortex of wild-type (WT) and glutathione peroxidase-1 (a major antioxidant enzyme) knockout (Gpx1(-/-)) mice at 8 and 24h postreperfusion to identify differential gene expression profile patterns and potential alternative injury cascades in the absence of Gpx1, a crucial antioxidant enzyme, in cerebral ischemia. Genes with at least ±1.5-fold change in expression at either time point were considered significant. Global transcriptomic analyses demonstrated that 70% of the WT-MCAO profile overlapped with that of Gpx1(-/-)-MCAO, and 28% vice versa. Critical analysis of the 1034 gene probes specific to the Gpx1(-/-)-MCAO profile revealed regulation of additional novel pathways, including the p53-mediated proapoptotic pathway and Fas ligand (CD95/Apo1)-mediated pathways; downplay of the Nrf2 antioxidative cascade; and ubiquitin-proteasome system dysfunction. Therefore, this comparative study forms the foundation for the establishment of screening platforms for target definition in acute cerebral ischemia intervention.
authors.affiliation: Menzies Research Institute, University of Tasmania, Hobart, TAS 7001, Australia.
authors.forename: Minghui Jessica
authors.initials: MJ
authors.lastname: Chen
authors.forename: Connie H Y
authors.initials: CH
authors.lastname: Wong
authors.forename: Zhao Feng
authors.initials: ZF
authors.lastname: Peng
authors.forename: Jayapal
authors.initials: J
authors.lastname: Manikandan
authors.forename: Alirio J
authors.initials: AJ
authors.lastname: Melendez
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Tan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crack
authors.forename: Nam Sang
authors.initials: NS
authors.lastname: Cheung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics; D020869:Gene Expression Profiling; D016158:Genes, p53; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
chemical_list: D053222:Fas Ligand Protein; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D043743:Ubiquitin-Protein Ligase Complexes; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse