Ligand-Activated Peroxisome Proliferator-Activated Receptor-γ Protects Against Ischemic Cerebral Infarction and Neuronal Apoptosis by 14-3-3∈ Upregulation

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. Methods and 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 14-3-3 is an element of was highly upregulated in rats treated with rosiglitazone. Upregulation of 14-3-3 is an element of 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 14-3-3 is an element of promoter and thereby increased 14-3-3 is an element of transcription. 14-3-3 is an element of Small interfering RNA abrogated the antiapoptotic actions of rosiglitazone or PPAR-gamma overexpression, whereas 14-3-3 is an element of recombinant proteins rescued brain tissues and N2-A cells from ischemia-induced damage and apoptosis. Elevated 14-3-3 is an element of 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 14-3-3 is an element of transcription. 14-3-3 is an element of Upregulation enhances sequestration of phosphorylated Bad and thereby suppresses apoptosis. (Circulation. 2009; 119: 1124-1134.)