A global transcriptomic view of the multifaceted role of glutathione peroxidase-1 in cerebral ischemic–reperfusion injury

• Published in: Free radical biology & medicine 2011-03, Vol.50 (6), p.736-748
• Main Authors: Chen, Minghui Jessica, Wong, Connie H.Y., Peng, Zhao Feng, Manikandan, Jayapal, Melendez, Alirio J., Tan, Theresa M., Crack, Peter J., Cheung, Nam Sang
• Format: Article
• Language: English
• Subjects: Animals; antioxidants; apoptosis; Apoptosis - genetics; cortex; Disease Models, Animal; Fas Ligand Protein - genetics; Free radicals; gene expression; Gene Expression Profiling; gene expression regulation; genes; Genes, p53; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Glutathione peroxidase 1; infarction; Infarction, Middle Cerebral Artery - genetics; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Inflammation; ischemia; Ischemic Attack, Transient - genetics; Ischemic Attack, Transient - metabolism; Ischemic Attack, Transient - pathology; Ischemic stroke; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray; microarray technology; Neurodegeneration; NF-E2-Related Factor 2 - genetics; Nuclear factor (erythroid-related 2)-like 2; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; pathogenesis; Polymerase Chain Reaction; Reactive Oxygen Species; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - surgery; screening; Signal Transduction; transcriptomics; Ubiquitin-Protein Ligase Complexes - genetics; Ubiquitin–proteasome pathway
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2010.12.025

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 24 h 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.