title: Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation.
abstract: BACKGROUND
  Thiazolidinediones have been reported to protect against ischemia-reperfusion injury. Their protective actions are considered to be peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-dependent; however, it is unclear how PPAR-gamma activation confers resistance to ischemia-reperfusion injury.
  
  
  RESULTS
  We evaluated the effects of rosiglitazone or PPAR-gamma overexpression on cerebral infarction in a rat model and investigated the antiapoptotic actions in the N2-A neuroblastoma cell model. Rosiglitazone or PPAR-gamma overexpression significantly reduced infarct volume. The protective effect was abrogated by PPAR-gamma small interfering RNA. In mice with knock-in of a PPAR-gamma dominant-negative mutant, infarct volume was enhanced. Proteomic analysis revealed that brain 14-3-3epsilon was highly upregulated in rats treated with rosiglitazone. Upregulation of 14-3-3epsilon was abrogated by PPAR-gamma small interfering RNA or antagonist. Promoter analysis and chromatin immunoprecipitation revealed that rosiglitazone induced PPAR-gamma binding to specific regulatory elements on the 14-3-3epsilon promoter and thereby increased 14-3-3epsilon transcription. 14-3-3epsilon Small interfering RNA abrogated the antiapoptotic actions of rosiglitazone or PPAR-gamma overexpression, whereas 14-3-3epsilon recombinant proteins rescued brain tissues and N2-A cells from ischemia-induced damage and apoptosis. Elevated 14-3-3epsilon enhanced binding of phosphorylated Bad and protected mitochondrial membrane potential.
  
  
  CONCLUSIONS
  Ligand-activated PPAR-gamma confers resistance to neuronal apoptosis and cerebral infarction by driving 14-3-3epsilon transcription. 14-3-3epsilon Upregulation enhances sequestration of phosphorylated Bad and thereby suppresses apoptosis.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Jui-Sheng
authors.initials: JS
authors.lastname: Wu
authors.forename: Wai-Mui
authors.initials: WM
authors.lastname: Cheung
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
authors.forename: Yi-Tong
authors.initials: YT
authors.lastname: Chen
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Fong
authors.forename: Hsin-Da
authors.initials: HD
authors.lastname: Tsai
authors.forename: Yu-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Jin-Jer
authors.initials: JJ
authors.lastname: Chen
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Teng-Nan
authors.initials: TN
authors.lastname: Lin
mesh_terms: D048948:14-3-3 Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D048948:14-3-3 Proteins; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone