Ligand-activated peroxisome proliferator-activated receptor-γ protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3e upregulation

Jui Sheng Wu, Wai Mui Cheung, Yau Sheng Tsai, Yi Tong Chen, Wen Hsuan Fong, Hsin Da Tsai, Yu Chang Chen, Jun Yang Liou, Song Kun Shyue, Jin Jer Chen, Y. Eugene Chen, Nobuyo Maeda, Kenneth K. Wu, Teng Nan Lin

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)

Abstract

Background-Thiazolidinediones have been reported to protect against ischemia-reperfusion injury. Their protective actions are considered to be peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent; however, it is unclear how PPAR-γ activation confers resistance to ischemia-reperfusion injury. Methods and Results-We evaluated the effects of rosiglitazone or PPAR-γ overexpression on cerebral infarction in a rat model and investigated the antiapoptotic actions in the N2-A neuroblastoma cell model. Rosiglitazone or PPAR-γ overexpression significantly reduced infarct volume. The protective effect was abrogated by PPAR-γ small interfering RNA. In mice with knock-in of a PPAR-γ dominant-negative mutant, infarct volume was enhanced. Proteomic analysis revealed that brain 14-3-3ε was highly upregulated in rats treated with rosiglitazone. Upregulation of 14-3-3ε was abrogated by PPAR-γ small interfering RNA or antagonist. Promoter analysis and chromatin immunoprecipitation revealed that rosiglitazone induced PPAR-γ binding to specific regulatory elements on the 14-3-3ε promoter and thereby increased 14-3-3ε transcription. 14-3-3ε Small interfering RNA abrogated the antiapoptotic actions of rosiglitazone or PPAR-γ overexpression, whereas 14-3-3ε recombinant proteins rescued brain tissues and N2-A cells from ischemia-induced damage and apoptosis. Elevated 14-3-3ε enhanced binding of phosphorylated Bad and protected mitochondrial membrane potential. Conclusions-Ligand-activated PPAR-γ confers resistance to neuronal apoptosis and cerebral infarction by driving 14-3-3ε transcription. 14-3-3e Upregulation enhances sequestration of phosphorylated Bad and thereby suppresses apoptosis.

Original languageEnglish
Pages (from-to)1124-1134
Number of pages11
JournalCirculation
Volume119
Issue number8
DOIs
Publication statusPublished - 2009 Mar 3

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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