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

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

説明

<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> Thiazolidinediones have been reported to protect against ischemia-reperfusion injury. Their protective actions are considered to be peroxisome proliferator–activated receptor-γ (PPAR-γ)–dependent; however, it is unclear how PPAR-γ activation confers resistance to ischemia-reperfusion injury. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> We evaluated the effects of rosiglitazone or PPAR-γ overexpression on cerebral infarction in a rat model and investigated the antiapoptotic actions in the N2-A neuroblastoma cell model. Rosiglitazone or PPAR-γ overexpression significantly reduced infarct volume. The protective effect was abrogated by PPAR-γ small interfering RNA. In mice with knock-in of a PPAR-γ dominant-negative mutant, infarct volume was enhanced. Proteomic analysis revealed that brain 14-3-3ε was highly upregulated in rats treated with rosiglitazone. Upregulation of 14-3-3ε was abrogated by PPAR-γ small interfering RNA or antagonist. Promoter analysis and chromatin immunoprecipitation revealed that rosiglitazone induced PPAR-γ binding to specific regulatory elements on the 14-3-3ε promoter and thereby increased 14-3-3ε transcription. 14-3-3ε Small interfering RNA abrogated the antiapoptotic actions of rosiglitazone or PPAR-γ overexpression, whereas 14-3-3ε recombinant proteins rescued brain tissues and N2-A cells from ischemia-induced damage and apoptosis. Elevated 14-3-3ε enhanced binding of phosphorylated Bad and protected mitochondrial membrane potential. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> Ligand-activated PPAR-γ confers resistance to neuronal apoptosis and cerebral infarction by driving 14-3-3ε transcription. 14-3-3ε Upregulation enhances sequestration of phosphorylated Bad and thereby suppresses apoptosis. </jats:p>

収録刊行物

  • Circulation

    Circulation 119 (8), 1124-1134, 2009-03-03

    Ovid Technologies (Wolters Kluwer Health)

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