| First Author | Wu JS | Year | 2009 |
| Journal | Circulation | Volume | 119 |
| Issue | 8 | Pages | 1124-34 |
| PubMed ID | 19221220 | Mgi Jnum | J:166007 |
| Mgi Id | MGI:4839436 | Doi | 10.1161/CIRCULATIONAHA.108.812537 |
| Citation | Wu JS, et al. (2009) Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation. Circulation 119(8):1124-34 |
| abstractText | 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 14-3-3epsilon 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. |
