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Analysis of function and regulation mechanism of expression of thrombomodulin, a regulating factor of blood coagulation, on surface of endothelial cells

Research Project

Project/Area Number 03833027
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 分子細胞生物学
Research InstitutionTeikyo University

Principal Investigator

ISHII Hidemi  Teikyo University, Faculty of Pharmaceutical Sciences, Department of Clinical Biochemistry, Associate Professor, 薬学部, 助教授 (50102710)

Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1992: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1991: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsvascular endothelial cells / regulation of blood coagulation / thrombomodulin / Protein C / regulation of expression / retinoic acid
Research Abstract

Normal endothelial cells repress blood coagulation during generation of anticoagulant factors and are inhibiting formation of thrombosis. Thrombomodulin (TM) expressed on the surface of endothelial cells forms complex with thrombin and inhibits procoagulant activity of thrombin such as fibrin formation, platelet activation and activation of coagulation factors V and VIII. By the formation of complex, activity to activate protein C is further induced and production of thrombin is inhibited by activated protein C. Thus, TM modurates procoagulant activity of thrombin to anticoagulant activity and functions as anticoagulant. Although the above mentioned functions of TM were suggested from in vitro expeiments using purified TM, role and function of TM on the surface of endothelial cells had not been identified.
In the present studies, it was indicated that 1. TM expressed on the surface of endothelial cells also formed complex with thrombin and the complex activated protein C on the surface, … More 2. the cofactor activity of TM to activate protein C on the cell surface was about 10 times higher than that of purified TM. We demonstrated that TM expressed on surface of endothelial cells effectively functions as anticoagulant. It was further revealed that 3. when endothelial cells were exposed to tumor necrosis factor (TNF) or interleukin-1 (IL-1), transcriptional level and protein synthesis of TM was reduced and the cofactor activity to activate protein C on the cell surface was also decreased, 4. treatment of endothelial cells with retinoic acid (vitamin A acid) increased transcription level, protein synthesis and the cofactor activity of TM, and 5. retinoic acid returned to normal level of TM on the cells surface even when TM level was reduced by exposure of the cells to TNF. We proposed that one of causes of thrombosis generation in tumor or inflammation could be due to decrease in TM expression by exposure to the cytokines, and suggested possibility of therapy by retinoic acid on thrombosis in the case of above deseases. Less

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (41 results)

All Other

All Publications (41 results)

  • [Publications] Ishii Hidemi: "Soluble heterogeneous thrombomoduin is derived from injured endothelial cells." Thromb.Haemost.,. 65. 618-623 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tanaka Akira: "Increased thrombomodulin values in plasma of diabetic men with microangiopathy." Clin.Chem.37. 269-272 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Wong,V.L.Y.: "Regional distribution of thrombomodulin in human brain." Brain Res.556. 1-5 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 石井 秀美: "血管内皮細胞が産生する血栓調節因子のサイトカインによる発現異常とそれへの対応" 日本網内系学会誌. 31. 345-353 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Sawada Kazuyoshi: "Changes in thrombomodulin level in plasma of endotoxin shocked rabbits." Thromb.Res.65. 199-210 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Uchiyama Hiroyuki: "Changes in plasma thrombomodulin antigen developing disseminated intravascular coagulation rabbits and preventive effect of heparin." Thromb.Res.65. 593-604 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Horie Shuichi: "Retinoic acid stimulates expression of thrombomodulin,a cell surface anti-coagulant glycoprotein,on human endothelial cells." Biochem.J.281. 149-154 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ishii Hidemi: "Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumore necrosis factor." Blood. 80. 2556-2562 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 石井 秀美: "プロテインC活性化におけるトロンボモジュリンの補酵素活性に対するリン脂質の促進効果" 臨床血液. 33. 745-749 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Steiner,M.: "Plasma thrombomodulin in patients with deep vein thrombosis." Thromb.Haemor.Dis.5. 47-49 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Hashimoto,Y.: "Cytokine regulation of hemostatic property and IL-6 production of human endothelial cells." Inflammation. 16. 613-621 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kawakami,M.: "Plasma thrombomodulin and a2-plasmin inhibitor-plasmin complex areelevated in active systemic lupus erythematosus." J.Rheumat.19. 1704-1709 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kamiguti,A.S.: "The role of venom heamorrhagin in spontaneous bleeding in Bothrops jararaca envenoming." Thromb.Haemost.67. 484-488 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ishii,H., Uchiyama,H. and Kazama,M: "Soluble heterogeneous thrombomodulin is derived from injured endothelial cells" Thromb. Haemst. 65. 618-623 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tanaka,A., Hiraishi,S., Ishii,H., Kazama,M. and Maezawa,H: "Increased thrombomodulin values in plasma of diabetic men with microangiopathy" Clin. Chem. 37. 269-272 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ishii,H., Kizaki,K., Hiraishi,S., Horie,S. and Kazama,M: "Abnormal expression by cytikines of pro- and anti-thrombotic factors produced in endothelial cells and a remedy for the abnormality" J. Jpn. Soc. R. E. S. 31. 345-353 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Wong,V.L.Y., Hofman,F.M., Ishii,H. and Fisher,M: "Regional distribution of thrombomodulin in human brain" Brain Res. 556. 1-5 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Sawada,K., Matumoto,H., Yamamoto,K., Kazama,M., Tahara,C., Ishii,H. and Abe,T: "Changes in thrombomodulin level in plasma of endotoxin shocked rabbits" Thromb. Res. 65. 199-210 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Uchiyama,H., Ohtani,D., Hiraishi,S., Horie,S., Ishii,H. and Kazama,M: "Changes in plasma thrombomodulin antigen developing disseminated intravascular coagulation rabbits and preventive effect of heparin" Thromb. Res. 65. 593-604 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Horie,S., Kizaki,K., Hiraishi,S., Ishii,H. and Kazama,M: "Retinoic acid stimulates expression of thrombomodulin, on endothelial cells ; Difference between up-regulation of thrombomodulin by retinoic acid and cAMP" Biochem. J. 281. 149-154 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ishii,H., Horie,S., Kizaki,K. and Kazama,M: "Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured endothelial cells exposed to tumor necrosis f actor" Blood. 80. 2556-2562 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ishii,H., Horie,S. and Kazama,M: "Acceleration of cofactor activity of thrombomodulin in protein C activation by phospholipid" Jpn. J. Clin. Hemat. 33. 745-749 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Steiner,M., Burstein,Ch., Anders,O., Ishii,H. Ernst,B: "Plasma thrombomodulin in patients with deep vein thrombosis" Thromb. Haemor. Dis. 5. 47-49 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Hashimoto,Y., Hirohata,S., Kashiwado,T., and Ishii,H.: "Cytokine regulation of hemostatic property and IL-6 production of human endothelial cells" Inflammation. 16. 613-621 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kawakami,M., Kitani,A., Hara,M., Harigai,M., Suzuki,K., Kawaguchi,Y., Ishii,H., Kazama,M., Kawagoe,M. and Nakamura,H: "Plasma thrombomodulin and alpha_2-plasmin inhibitor-plasmin complex are elevated in active systemic lupus erythematosus" J. Rheumat. 19. 1704-1709 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kamiguti,A.S., Rugman,F.P., Theakston,R.D.G., Franca,F.O.S., Ishii,H., Hay,C.R.M. and BIASG: "The role of venom heamorrhagin in spontaneous bleeding in Bothrops jararaca envenoming" Thromb. Haemost. 67. 484-488 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ishii Hidemi: "Soluble heterogeneous thrombomoduin is derived from injured endothelial cells." Thromb.Haemost.,. 65. 618-623 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] Tanaka Akira: "Increased thrombomodulin values in plasma of diabetic men with microangiopathy." Clin.Chem.37. 269-272 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] Wong,V.L.Y.: "Regional distribution of thrombomodulin in human brain." Brain.Res.556. 1-5 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] 石井 秀美: "血管内皮細胞が産生する血栓調節因子のサイトカインによる発現異常とそれへの対応" 日本網内系学会誌. 31. 345-353 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sawada Kazuyoshi: "Changes in thrombomodulin level in plasma of endotoxin shocked rabbits." Thromb.Res.65. 199-210 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Uchiyama Hiroyuki: "Changes in plasma thrombomodulin antigen developing disseminated intravascular coagulation rabbis and preventive effect of heparin." Thromb.Res.65. 593-604 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Horie Shuichi: "Retinoic acid stimulates expression of thrombomodulin,a cell surface anti-coagulant glycoprotein,on human endothelial cells." Biochem.J.281. 149-154 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Ishii Hidemi: "Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumore necrosis factor." Blood. 80. 2556-2562 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 石井 秀美: "プロテインC活性化におけるトロンボモジュリンの補酵素活性に対するリン脂質の促進効果" 臨床血液. 33. 745-749 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Steiner,M.: "Plasma thrombomodulin in patients with deep vein thrombosis." Thromb.Haemor.Dis.5. 47-49 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hashimoto,Y.: "Cytokine regulation of hemostatic property and IL-6 production of human endothelial cells." Inflammation. 16. 613-621 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kawakami,M.: "Plasma thrombomodulin and a2-plasmin inhibitor-Plasmin complex areelevated in active systemic lupus erythematosus." J.Rheumat.19. 1704-1709 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kamiguti,A.S.: "The role of venom heamorrhagin in spontaneous bleeding in Bothrops jararaca envenoming." Thromb.Haemost.67. 484-488 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 石井 秀美: "血管内皮細胞が産生する血栓調節因子のサイトカインによる発現異常とそれへの対応" 日本網内系学会誌. 31. 45-53 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Shuichi Horie: "Retinoic acid stimulates expression of thrombomodulin,a cell surface antiーcoagulant glycoprotein,on human endothelial cells." Biochemical Journal. 281. 149-154 (1992)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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