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

Free Radic Biol Med. 2011 Mar 15;50(6):736-48. doi: 10.1016/j.freeradbiomed.2010.12.025. Epub 2010 Dec 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Disease Models, Animal
  • Fas Ligand Protein / genetics
  • Gene Expression Profiling
  • Genes, p53
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism*
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / metabolism*
  • Infarction, Middle Cerebral Artery / pathology
  • Inflammation
  • Ischemic Attack, Transient / genetics
  • Ischemic Attack, Transient / metabolism*
  • Ischemic Attack, Transient / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • Oligonucleotide Array Sequence Analysis
  • Oxidation-Reduction
  • Polymerase Chain Reaction
  • Reactive Oxygen Species
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Reperfusion Injury / surgery
  • Signal Transduction
  • Ubiquitin-Protein Ligase Complexes / genetics

Substances

  • Fas Ligand Protein
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Ubiquitin-Protein Ligase Complexes