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Regulation of NO synthesis by the urea cycle enzymes

Research Project

Project/Area Number 10557020
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Pathological medical chemistry
Research InstitutionKumamoto University

Principal Investigator

MORI Masataka  Kumamoto University, School of Medicine, Professor, 医学部, 教授 (40009650)

Co-Investigator(Kenkyū-buntansha) HIROSI Nonoguchi  Kumamoto University, School of Medicine, Associate Professor, 医学部, 講師 (30218341)
TOMITA Kimio  Kumamoto University, School of Medicine, Professor, 医学部, 教授 (40114772)
GOTOH Tomomi  Kumamoto University, School of Medicine, Assistant Professor, 医学部, 助手 (20264286)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2000: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 1998: ¥5,600,000 (Direct Cost: ¥5,600,000)
Keywordsarginase / apoptosis / NO / macrophage / NO synthase / arginine / 一酸化窒素合成酵素 / アルギニノコハク酸合成酵素 / アルギニノコハク酸リアーゼ
Research Abstract

Nitric oxide (NO) is a messenger molecule functioning in vascular regulation, immunity, neurotransmission and others, and has been implicated in many diseases. NO is synthesized from arginine by NO synthase (NOS), and the availability of arginine has been shown to be one of the rate-limiting factors in NO production. Citrulline formed as a by-product of the NOS reaction can be recycled to arginine by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL). We found that AS and AL are coinduced with inducible NOS (iNOS) in macrophages of rat and mouse tissues after LPS administration. Coinduction of iNOS and AS was also seen in immunostimulated rat glioma C6 cells and rat neuronal PC12 cells. In these cells, NO was synthesized from citrulline as well as from arginine, indicating operation of the citrulline-NO cycle. Coinduction of endothelial NOS (eNOS), AS and AL was found in aorta of streptozotocine-induced diabetic rats. eNOS was also found to be induced in astrocytes by l … More ow concentrations of LPS, and expression of the citrulline-NO cycle is to be tested. Cationic amino acid transporter (CAT)-2 was induced in macrophages, but not in C6 and PC12 cells. On the other hand, arginase may downregulate NO production by depleting arginine. We found that iNOS and arginase isoforms (type I and II) are coinduced by LPS in rodent tissues and cultured macrophages. In contrast, arginase was not induced in C6 and PC12 cells. When mouse macrophage-like RAW 264.7 cells were treated with LPS and interferon-γ, iNOS was induced, NO was produced and apoptosis followed. When iNOS and arginase II were coinduced, NO production was decreased and apoptosis was prevented. Furthermore, the cells transfected with an arginse I or II expression plasmid were rescued from apoptosis. These results indicate that NO production is regulated by uptake, recycling and degradation of arginine, and suggest that these enzymes can be good targets to regulate NO production in diseases in which oveproduction or impaired production of NO is implicated. Less

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (46 results)

All Other

All Publications (46 results)

  • [Publications] Javeshghani,D. et al.: "Regulation of diaphragmatic nitric oxide synthase expression during hypobaric hypoxia"Am.J.Physiol.. 279. L520-L527 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Zhang,W.Y., et al.: "Coinduction of inducible nitric oxide synthase and arginine recycling enzymes in cytokine-stimulated PC12 cells and high output production"Mol.Brain Res.. 10. 1-8 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Daniel,E.E., et al.: "Arginosuccinate synthetase, arginosuccinate lyase and NOS in canine gastrointestinal tract : immunocytochemical studies"Neurogastroenterol.Mot.. 12. 317-334 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori,M.and Gotoh,T.: "Regulation of nitric oxide production by arginine metabolic enzymes"Biochem.Biophys.Res.Commun.. 275. 715-719 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Koshiyama,Y., et al.: "Expression and localization of enzymes of arginase metabolism in the rat eye"Curr.Eye Res.. 20. 313-321 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwase,K., et al.: "Induction of endothelial nitric oxide synthase in rat brain astrocytes by systenic lipopolysaccharide treatment"J.Biol.Chem.. 275. 11929-11933 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Gotoh,T.and Mori,M.: "Arginase II down-regulates NO production and prevents NO-mediated apoptosis in murine macrophage-derived RAW 264.7 cells"J.Cell Biol.. 144. 427-434 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ozaki,M., et al.: "Expression of arginase II and related enzymes in the rat small intestine and kidney"J.Biochem.. 125. 586-593 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Salimuddin, et al.: "Regulation of the gene for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide."Am.J.Physiol.. 277. E110-E117 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mahmoud,Y.A.-G., et al.: "Expression of inducible nitric oxide synthase and enzymes of arginine metabolism in Fusarium kyushuense-exposed mouse lung"Nitric Oxide. 3. 302-311 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori,M. and Gotoh,T.: "Regulation of NO production and NO-mediated apoptosis by arginae isoforms (Proceedings of the Nitric Oxide Symposium)"National University of Singapore 145-155, 1999. 145-155 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwase,K.,et al.: "Precise distributin of neuronal nitric oxide synthase mRNA in the rat brain revealed by non-radioisotopic in situ hybridization"Mol.Brain Res.. 53. 1-12 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori,M. and Gotoh,T.: "Nitric Oxide"Academic Press. 10 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwase, K., et al.: "Induction of endothelian nitric oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment"J.Biol.Chem.. 275. 11929-11933 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Javeshghani, D.et al.: "Regulation of diaphragmatic nitric oxide synthase expression during hypobaric hypoxia"Am.J.Physiol.. 279. L520-L527 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Zhang, W.Y., et al.: "Coinduction of inducible nitric oxide synthase and arginine recycling enzymes in cytokine-stimulated PC12 cells and high output production"Mol.Brain Res.. 10. 1-8 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Daniel, E.E., et al.: "Arginosuccinate synthase, arginosucchinate lyase and NOS in canine gastrointestinal tract : immunocytochemical studies"Neurogastroenterol.Mot.. 12. 317-334 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori, M.and Gotoh, T.: "Regulation of nitric oxide production by arginine metabolic enzymes"Biochem.Biophys.Res.Commun.. 275. 715-719 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Koshiyama, Y., et al.: "Expression and localization of enzymes of arginase metbolism in the rat eye"Curr.Eye Res.. 20. 313-321 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori, M.and Gotoh, T.: "Relation between arginae activity and nitoric oxide production"Nitric Oxide, Academic Press. 200-208 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Gotoh, T.and Mori, M.: "Arginase II down-regulates NO production and prevents NO-mediated apoptosis in murine macrophage-derived RAW 264.7 cells."J.Cell Biol.. 144. 427-434 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ozaki, M., et al.: "Expression of arginase II and related enzymes in the rat small intestine and kidney"J.Biochem.. 125. 586-593 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Salimuddin, et al.: "Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide"Am.J.Physiol.. 277. E110-E117 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mahmoud, Y.A.-G., et al.: "Expression of inducible nitric oxide synthase and enzymes of arginine metabolism in Fusarium kyushuense-exposed mouse lung"Nitric Oxide. 3. 302-311 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori, M.and Gotoh, T.: "Regulation of NO production and NO-mediated apoptosis by arginae isoforms (Proceedings of the Nitric Oxide Symposium)"National University of Singapore. 145-155 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwase, K., et al.: "Precise distributin of neuronal nitric oxide synthase mRNA in the rat brain revealed by non-radioisotopic in situ hybridization"Mol.Brain Res.. 53. 1-12 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Louis, C.A., et al.: "Distinct arginase isoforms expressed in primary and transformed macrophages : regulation by oxygen tension"Am.J.Physiol.. 274. R775-R782 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori, M., et al.: "(Review) Regulation of the urea cycle enzyme genes in nitric oxide synthesis"J.Inher.Metab.Dis.. (Suppl.1) 21. 59-71 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyanaka, K., et al.: "Immunohistochemical localization of arginase II and other enzymes of arginine metabolism in rat kidney and liver"Histochem.J.. 30. 741-751 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Javeshghani,D. et al.: "Regulation of diaphragmatic nitric oxide synthase expression during hypobaric hypoxia"Am.J.Physiol.. 279. L520-L527 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Zhang,W.Y., et al. : "Coinduction of inducible nitric oxide synthase and arginine recycling enzymes in cytokine-stimulated PC12 cells and high output production"Mol.Brain Res.. 10. 1-8 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Daniel,E.E., et al.: "Arginosuccinate synthetase, arginosuccinate lyase and NOS in canine gastrointestinal tract : immunocytochemical studies"Neurogastroenterol.Mot.. 12. 317-334 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mori,M.and Gotoh,T.: "Regulation of nitric oxide production by arginine metabolic enzymes"Biochem.Biophys.Res.Commun.. 275. 715-719 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koshiyama,Y., et al.: "Expression and localization of enzymes of arginase metabolism in the rat eve"Curr.Eye Res.. 20. 313-321 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Iwase,K., et al.: "Induction of endothelial nitric oxide synthase in rat brain astrocytes by systenic lipopolysaccharide treatment"J.Biol.Chem.. 275. 11929-11933 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mori,M.and Gotoh,T.: "Nitric Oxide"Academic Press. 10 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Gotoh,T. and Mori,M.: "Arginase II down-regulates NO production and prevents NO-mediated apoptosis in murine macrophage-derived RAW264.7 cells"J. Cell Biol.. 144. 427-434 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ozaki,M.,Gotoh,T.,et al.: "Expression of arginase II and related enzymes in the rat small intestine and kidney"J. Biochem.. 125. 586-593 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Salimuddin,Nagasaki,A.,et al.: "Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide"Am. J. Physiol.. 177. E110-E117 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mahmoud,Y. A. -G.,Harada,K.,et al.: "Expression of inducible nitric oxide synthase and enzymes of arginine metabolism in Fusarium kyushuense-exposed mouse lung"Nitric Oxide. 3. 302-311 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mori,M. and Gotoh,T.: "Regulation of NO production and NO-mediated apoptosis by arginase isoforms Proceedings of the Nitric Oxide Symposium"National University of Singapore. 145-155 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Iwase,K.,Miyanaka,K.,et al.: "Induction of endothelian niytric oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment"J. Biol. Chem.,. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Iwase,K.,et al.: "Precise distribution of neuronal nitric oxide synthase mRNA in the rat brain revealed by non-radioisotopic in situ hybridization" Mol.Brain Res.53. 1-12 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Louis,C.A.,et al.: "Distinct arginase isoforms expressed in primary and transformaed macrophages: regulation by oxygen tension" Am.J.Physiol.274. R775-R782 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mori,M.,et al.: "REVIEW: Regulation of the urea cycle enzyme genes in nitric oxide synthesis" J.Inher.Metab.Dis.,(Suppl.1). 21. 59-71 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Miyanaka,K.,et al.: "Immunohistochemical localization of arginase II and other enzymes of arginine metabolism in rat kidney and liver" Histochem.J.30218341. 741-751 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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