Published Online
on February 16, 2009

A more recent version of this article appeared on March 3, 2009

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Submitted on August 3, 2008
Accepted on December 22, 2008

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^*, and 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.

^* To whom correspondence should be addressed. E-mail: kkgo{at}nhri.org.tw or bmltn{at}ibms.sinica.edu.tw.

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.

Key words: apoptosis • infarction • stroke • PPAR gamma

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Clinical Summaries
Circulation 2009 119: 1067-1068. [Extract] [Full Text]

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