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

Minghui Jessica Chen, Connie Hoi Yee Wong, Zhao Feng Peng, Jayapal Manikandan, Alirio J Melendez, Theresa M Tan, Peter John Crack, Nam Sang Cheung

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16 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)736 - 748
Number of pages13
JournalFree Radical Biology and Medicine
Volume50
Issue number6
DOIs
Publication statusPublished - 2011
Externally publishedYes

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