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(Circulation. 2009;119:1124-1134.)
© 2009 American Heart Association, Inc.

Stroke

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

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

From the Institute of Biomedical Sciences (J.-S.W., W.-M.C., Y.-T.C., W.-H.F., H.-D.T., Y.-C.C., S.-K.S., J.-J.C., T.-N.L.), Academia Sinica, Taipei, Taiwan; Graduate Institute of Life Sciences (J.-S.W.), National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Clinical Medicine (Y.-S.T.), National Cheng Kung University Medical College, Tainan, Taiwan; National Health Research Institutes (J.-Y.L., K.K.W.), Zhunan, Taiwan; Cardiovascular Center (Y.E.C.), University of Michigan Medical Center, Ann Arbor, Mich; Department of Pathology and Laboratory Medicine (N.M.), University of North Carolina, Chapel Hill, NC; and University of Texas Health Science Center (K.K.W.), Houston, Tex.

Correspondence to Kenneth K. Wu, MD, PhD, National Health Research Institutes, Zhunan Township, Miaoli County 350, Taiwan (e-mail kkgo{at}nhri.org.tw); or Teng-nan Lin, PhD, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan (e-mail bmltn@ibms.sinica.edu.tw).

Received August 3, 2008; accepted December 22, 2008.

Background— Thiazolidinediones have been reported to protect against ischemia-reperfusion injury. Their protective actions are considered to be peroxisome proliferator–activated receptor- (PPAR-)–dependent; however, it is unclear how PPAR- activation confers resistance to ischemia-reperfusion injury.

Methods and Results— We evaluated the effects of rosiglitazone or PPAR- overexpression on cerebral infarction in a rat model and investigated the antiapoptotic actions in the N2-A neuroblastoma cell model. Rosiglitazone or PPAR- overexpression significantly reduced infarct volume. The protective effect was abrogated by PPAR- small interfering RNA. In mice with knock-in of a PPAR- dominant-negative mutant, infarct volume was enhanced. Proteomic analysis revealed that brain 14-3-3 was highly upregulated in rats treated with rosiglitazone. Upregulation of 14-3-3 was abrogated by PPAR- small interfering RNA or antagonist. Promoter analysis and chromatin immunoprecipitation revealed that rosiglitazone induced PPAR- binding to specific regulatory elements on the 14-3-3 promoter and thereby increased 14-3-3 transcription. 14-3-3 Small interfering RNA abrogated the antiapoptotic actions of rosiglitazone or PPAR- overexpression, whereas 14-3-3 recombinant proteins rescued brain tissues and N2-A cells from ischemia-induced damage and apoptosis. Elevated 14-3-3 enhanced binding of phosphorylated Bad and protected mitochondrial membrane potential.

Conclusions— Ligand-activated PPAR- confers resistance to neuronal apoptosis and cerebral infarction by driving 14-3-3 transcription. 14-3-3 Upregulation enhances sequestration of phosphorylated Bad and thereby suppresses apoptosis.

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CLINICAL PERSPECTIVE

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