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. 14-3-3ε Upregulation enhances sequestration of phosphorylated Bad and thereby suppresses apoptosis.