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

• Published in: Circulation (New York, N.Y.) Vol. 119; no. 8; pp. 1124 - 1134
• Main Authors: WU, Jui-Sheng, CHEUNG, Wai-Mui, CHEN, Y. Eugene, MAEDA, Nobuyo, WU, Kenneth K, LIN, Teng-Nan, TSAI, Yau-Sheng, CHEN, Yi-Tong, FONG, Wen-Hsuan, TSAI, Hsin-Da, CHEN, Yu-Chang, LIOU, Jun-Yang, SHYUE, Song-Kun, CHEN, Jin-Jer
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 03.03.2009
• Subjects: 14-3-3 Proteins - biosynthesis; 14-3-3 Proteins - genetics; 14-3-3 Proteins - physiology; Animals; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Blood and lymphatic vessels; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Cardiology. Vascular system; Cell Line, Tumor; Cerebral Infarction - metabolism; Cerebral Infarction - pathology; Cerebral Infarction - prevention & control; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Ligands; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; PPAR gamma - biosynthesis; PPAR gamma - genetics; PPAR gamma - physiology; Rats; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Up-Regulation - drug effects; Up-Regulation - physiology; Vascular diseases and vascular malformations of the nervous system; Cerebral infarction; Nervous system diseases; Stroke; Infarct; infarction; Cardiovascular disease; PPAR gamma; Peroxisome proliferator; Cerebral disorder; Vascular disease; Ischemia; Central nervous system disease; Cerebrovascular disease; Apoptosis
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.108.812537

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. 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. 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.