Role of ORP150 in hypoxia/ischemia-induced neuronal cell death

• Project/Area Number: 10680703
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Osaka University
• Principal Investigator: TAMATANI Michio Osaka University Graduate School of Medicine, Lecturer, 医学系研究科, 助教授 (30294052)
• Co-Investigator(Kenkyū-buntansha): OGAWA Satoshi Kanazawa University School of Medicine, Professor, 医学部, 教授 (90283746) ; TOHYAMA Masaya Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (40028593)
• Project Period (FY): 1998 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
• Keywords: ORP150 / Neuronal cell death / Ischemia / hypoxia

Research Abstract

The role of 150-kDa oxygen regulated protein (ORP150) in hypoxia/ischemia-induced neuronal death was investigated. In cultured rat cortical neurons, cell death was accelerated by hypoxia with no obvious induction of ORP150, whereas cell viability was well maintained in cultured astrocytes with marked induction of ORP150. Adenovirus-mediated overexpression of ORP150 in cortical neurons resulted in the marked increase of ORP150 accompanied in parallel with restoration of cell viability under hypoxia. The introduction of antisense structure of ORP150 into astrocytes inhibited the induction of ORP150 under hypoxic condition and resulted in decreased cell viability. The tolerance of neurons given by ORP150 overexpression was observed in the hypoxic environment, but not in other apoptotic paradigm caused by heat shock or hydrogen peroxide. In vivo experiments revealed that the induction of ORP150 was observed in neurons as well as in astrocytes after the unilateral occlusion of the middle cerebral artery (MCA), as detected by immunohistochemical and in-situ hybridization analysis. Furthermore, to further explore the role of ORP150 in regulation of ischemic/hypoxic neuronal death in vivo, we generated transgenic mice expressing ORP150 under control of PDGF promoter, which forced expression uniquely in neurons. Profound protection against hypoxic insults in vitro and major decrease in infarct volume after permanent MCA occlusion was observed in ORP150 transgnic mice. These data suggest that ORP150 may play a protective role in neurons against ischemic/hypoxic insults.

Research Products

• [Publications] Tamatani,M,Matsuyama T,Yamaguchi A,Mitsuda N et al.: "Hypoxia/ischemia-induced neuronal death : neuroprotective properties of ORP150 "Nature Medicine. (In press). (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yamaguchi A,Tamatani M,Matsuzaki H,Namikawa K et al.: "Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53."Journal of Biological Chemistry. (In press). (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ohkubo N,Mitsuda N,Tamatani M,Yamaguchi A et al.: "Apoprotein E4 stimulates CREB's transcriptional Activity through the ERK pathway."Journal of Biological Chemistry. (In press). (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Matsuzaki H,Tamatani M,Yamagu,Namikawa K,Kiyama H et al.: "Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity : Signal transduction cascades."FASEB Journal. (In press). (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tamatani M,Mitsuda N,Matsuzaki H,Okado Miyake S et al.: "A Pathway of Neuronal Apoptosis Induced by H/R : Roles of NFkB and Bcl-2."Journal of Neurochemistry. 75. 683-693 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ozawa K,Kuwabara K.,Tamatani,M,Takatsuji K,Tsukamoto Y et al.: "ORP150 (150kDa Oxygen-Regulated Protein) supresses hypoxia-induced apoptotic cell death."Journal of Biological Chemistry. 274. 6397-6404 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tamatani M, Matsuyama T, Yamaguchi A, Mitsuda N, Tsukamoto Y, Taniguchi M, Che YH, Ozawa K, Hori O, Nishimura H, Yamashita A, Okabe M, Yanagi H, Stern DM, Ogawa S, Tohyama M: "ORP 150 protects against hypoxia/ischemia-induced neuronal death."Nat. Med. 7. 317-323 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Matsuzaki H, Tamatani M, Yamaguchi A, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M: "Vascular Endothelial Growth Factor Rescues Hippocampal Neurons from Glutamate-Induced Toxicity : Signal Transduction Cascades."FASEB J. (in press.). (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Mitsuda N, Ohkubo N,Tamatani M, Lee YD, Taniguchi M, Namikawa K, Kiyama H, Yamaguchi A, Sato N, Ogihara T, Vitek MP, Tohyama M.: "Activated CREB regulates neuronal expression of presenilin-1."J.Biol.Chem.. (In press.). (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M.: "Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53."J.Biol.Chem.. 276. 5256-5264 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ohkubo N, Mitsuda N, Tamatani M, Yamaguchi A, Lee YD, Ogihara T, Vitek MP, Tohyama M: "Apoprotein E4 stimulates CREB's transcriptional Activity through the ERK pathway."J.Biol.Chem.. 276. 3034-3053 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tamatani M, Mitsuda N, Matsuzaki H, Okado H, Miyake S, Vitek MP, Yamaguchi A, Tohyama M.: "A Pathway of Neuronal Apoptosis Induced by H/R : Roles of NFkB and Bcl-2."J.Neurochem.. 75. 683-693 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T: "Induction of aquaporin-4 mRNA after middle cerebral artery occlusion in rat."Brain Res.Mol.Brain.Res.. 78. 131-137 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Bando Y, Ogawa S, Yamauchi A, Kuwabara K, Ozawa K, Tamatani M, Yanagi H, Tohyama M.: "The 150 kDa Oxygen-regulated protein (ORP 150) functions as a novel molecular chaperone in the protein transport of the MDCK cells Am."J.Physiol.. 278. C1172-1182 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Che YH, Tamatani M, Tohyama M.: "Changes in mRNA for postsynaptic density-95 (PSD-95) and carboxy-terminal PDZ ligand of neuronal nitric oxide synthase following facial nerve transection."Brain Res.Mol.Brain.Res.. 76. 325-35 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Niitsu Y, Hori O, Yamaguchi A, Bando Y, Tamatani M, Ozawa K, Ogawa S, Tohyama M.: "Exposure of cultured primary rat astrocytes to hypoxia results in intracellular glucose depletion and induction of glycolytic enzymes."Brain Res.Mol.Brain Res.. 74. 26-34 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Matsuzaki H, Tamatani M, Mitsuda N, Namikawa K, Kiyama H, Miyake S, Tohyama M.: "Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitrc oxide in primary hippocampal neurons."J.Neurochem.. 73. 2037-46 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tamatani M, Che, YH, Matsuzaki H, Ogawa S, Okado H, Miyake S, Mizuno T, Tohyama M.: "Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NF kappa B activation in primary hippocampal neurons."J.Biol.Chem.. 274. 8531-8538 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ozawa K, Kuwabara K, Tamatani M, Takatsuji K, Tsukamoto Y, Kaneda S, Yanagi H, Stern DM, Eguchi Y, Tsujimoto Y, Ogawa S, Tohyama M.: "150-kDa oxygen-regulated protein (ORP150) suppresses hypoxia-induced apoptotic cell death."J.Biol.Chem.. 274. 6397-6404 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tamatani,M,Matsuyama T,Yamaguchi A,Mitsuda N et al.: "ORP150 protects neurons against hypoxia/ischemia-induced cell death"Nature Medicine. (In Press). (2001)
• [Publications] Yamaguchi A,Tamatani M,Matsuzaki H,Namikawa K et al.: "Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53."Journal of Biological Chemistry. (In Press). (2001)
• [Publications] Ohkubo N,Mitsuda N,Tamatani M,Yamaguchi A et al.: "Apoprotein E4 stimulates CREB's transcriptional Activity through the ERK pathway."Journal of Biological Chemistry. (In Press). (2001)
• [Publications] Matsuzaki H,Tamatani M,Yamagu Namikawa K,Kiyama H et al.: "Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity : Signal transduction cascades."FASEB Journal. (In Press). (2001)
• [Publications] Tamatani M,Mitsuda N,Matsuzaki H,Okado Miyake S et al.: "A Pathway of Neuronal Apoptosis Induced by H/R : Roles of NFkB and Bcl-2."Journal of Neurochemistry. 75. 683-693 (2000)
• [Publications] Ozawa K,Kuwabara K.,Tamatani,M,Takatsuji K,Tsukamoto Y et al.: "ORP150 (150 kDa Oxygen-Regulated Protein) supresses hypoxia-induced apoptotic cell death."Journal of Biological Chemistry. 274. 6397-6404 (1999)
• [Publications] K.Ozawa,K.Kuwabara,M.Tamatani,K.Takatsuji,Y.Tsukamoto et al.: "ORP150 (150 kDa Oxygen-Regulated Protein) supresses hypoxia-induced apoptotic cell death"Journal of Biological Chemistry. 274. 6397-6404 (1999)
• [Publications] M.Tamatani,Y.Che,H.Matsuzaki,A.Ogawa,H.Okado,S.Miyake et al.: "TFN induces Bcl-2 and Bcl-x expression through NFkB activation in primary hlppocampal neurons"Journal of Biological Chemistry. 274. 8531-8538 (1999)
• [Publications] H.Matsuzaki,M.Tamatani,N.Mitsuda,K.Namikawa,H.Kiyama et al.: "Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric * primary hippocampal neurons"Journal of Neurochemistry. 73. 2037-2046 (1999)
• [Publications] Y.Niitsu,O.Hori,A.Yamaguchi,Y.Bando,K.Ozawa,M.Tamatani et al.: "Exposure of cultured primaru rat astrocytes to hypoxia results in intracellular glucose depletion and in* of glycolytic enzymes"Molecular Brain Research. 74. 26-34 (1998)
• [Publications] YH.Che,M.Tamatani,T.Yamashita,F.Gomi,S.Ogawa,M.Tohyama.: "Changes of protein inhibitor of neuronal nitric oxide synthase mRNA following facial nerve transection"Journal of Chemical Neuroanatomy. 17. 199-206 (2000)
• [Publications] YH.Che,M.Tamatani,M.Tohyama.: "Changes in mRNA for postsynaptic density-95 (PSD-95) and carboxy-terminal PDZ ligand of neurona oxide synthase (CAPON) following facial nerve transection"Molecular Brain Reasearch. (in press).
• [Publications] K.Ozawa,K.Kuwabara,M.Tamatani,K.Takatsuji,Y.Tsukamoto et al.: "ORP150(150kDa Oxygen-Regulated Protein)supresses hypoxia-induced apoptotic cell death." Journlar of Biological Chemistry. (In Press). (1999)
• [Publications] M.Tamatani,Y.Che,H.Matsuzaki,S.Ogawa,H.Okado,S.Miyake et al.: "TNF induces Bcl-2 and Bcl-x expression through NFkB activation in primary hlppocampalneurons" Journlar of Biological Chemistry. (In Press). (1999)
• [Publications] M.Tamatani,S.Ogawa,G.Nunez,M.Tohyama: " Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide." Cell Death and Differentiation. 5. 911-919 (1998)
• [Publications] M.Tamatani,S.Ogawa、,Y.Niitsu,M.Tohyama.: "Involvement of Bcl-2 family and caspase-3-like proteases in NO-mediated neuronal apoptosis." Journlar of Neurochemistry. 71. 1588-1596 (1998)
• [Publications] M.Tamatani,S.Ogawa,M.Tohyama: "Roles of Bcl-2 and caspases in hypoxia-induced neuronal cell death:a possible neuroprotective mechanism of peptide growth factors." Molecular Brain Research. 58. 27-39 (1998)
• [Publications] T.Yamashita,M.Tamatani,M.Taniguchi,T.Yoshiminem,et al.: "Reguitation of Na/Myo-inositol cotransporter gene expression in hypoglycemic rat hippocampus" Molecular Brain Research. 57. 167-172 (1998)