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2003 Fiscal Year Final Research Report Summary

Transcriptional repression of PAI-1 gene expression by leptin receptor signal-mediated mechanisms.

Research Project

Project/Area Number 13670209
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionHAMAMATSU UNIVERSITY SCHOOL OF MEDICINE

Principal Investigator

IHARA Hayato  Hamamatsu Univ., Sch. Med. Dept. Physioi., Research Associate, 医学部, 助手 (00223298)

Co-Investigator(Kenkyū-buntansha) URANO Tetsumei  Hamamatsu Univ., Sch. Med. Dept. Physiol., Professor, 医学部, 教授 (50193967)
Project Period (FY) 2001 – 2003
KeywordsLeptin / Leptin receptor / PAI-1 / Adipocytes / obese mice
Research Abstract

Obese patients are at risk for development of cardiovascular disease, which can in part be explained by disturbances in the haemostatic and fibrinolytic systems. Recently, it has been demonstrated that the adipocyte itself is able to produce a primary fibrinolytic inhibitor, PAI-1, possibly accounting for the elevated PAI-1 levels in obesity. We hypothesized that leptin receptor signal transduction pathway might regulate PAI-1 gene expression in adipocytes, which could be activated by leptin secreted from these cells. Administration of recombinant leptin to ob/ob genetic obese mice not only caused reduction of plasma levels of PAI-1 but also repression of PAI-1 gene expression in abdominal fat, subcutaneous fat tissues, and lung tissue after 6 hr and 24 hr treatments. Cotransfection of 3T3-L1 preadipocyte with 5-PAI-1/Luc reporter and leptin expression vectors revealed that PAI-1 promoter activities were repressed in a dose-dependent manner. These results suggested that exogenous addition of leptin caused repression of PAI-1 expression in vivo and in vitro. Adipocytes express at least two kinds of leptin receptors ; long-and short-form. To identify the leptin receptor (LepR) involved in repression of PAI-1 gene expression, 3T3-L1 preadipocyte were transfected with leptin, and either short-or long-form LepR expression vectors, and then luciferase activities were measured after 48-hr incubation. Transfection in combination with leptin and short-form LepR expression vectors reduced PAI-1 gene transcriptional activities to 70〜75% of control value, while the transcriptional activities were up-regulated 1.8〜2 fold by transfection with leptin and long-form LepR expression vectors. These results suggested that decreased PAI-1 gene expression by leptin treatment was due to the short-form LepR signaling-mediated mechanisms.

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Ihara, H. et al.: "Induction of plasminogen activator inhibitor-1(PAI-1) gene expression in adipocytes by thiazolidinediones"FASEB J.. 15. 1233-1235 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagai, N. et al.: "Tissue-type plasminogen activator enhances neuronal death induced by oxygen-glucose-deprivation in culture."J.Cerebral Blood Flow and Metabolism. 21. 631-634 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Urano, T. et al.: "The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type 1"J.Biol.Chem.. 276. 24690-24696 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Pawlak, R. et al.: "The differential effect of angiotensin II and angiotensin 1-7 on norepinephrine, epinephrine, and dopamine concentrations in rat hypothalamus : the involvement of angiotensin receptors."Brain Res.Bull.. 54. 689-694 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Suzuki, Y. et al.: "Bezafibrate attenuates the overexpression of plasminogen activator inhibitor-1 messenger RNA by a combination of mono-unsaturated fatty acid and insulin in HepG2 cells."Life Sci.. 68. 1827-1837 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Pawlak, R. et al.: "Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice."Neuroscience. 113. 995-1001 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagai, N. et al.: "Tissue-type plasminogen activator has paradoxical roles in forcal cerebral ishemic injury by thrombotic middle cerebral artery occlusion with mild or severe photochemical damage in mice"J.Cerebral Blood Flow and Metabolism. 22. 648-651 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Zhao, B-Q et al.: "Essential role of endogenous tissue plasminogen activator via matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after forcal cerebral ischemia in mice."Blood. In press.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Suzuki Y., Urano T., Ihara H., Nakajima T., Nagai N., Takada Y., Taminato T., Takada A.: "Bezafibrate attenuates the overexpression of plasminogen activator inhibitor-1 messenger RNA by a combination of mono-unsaturated fatty acid and insulin in HepG2 cells"Life Sci.. 68. 1827-1837 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagai, N., Yamamoto, S., Tsuboi, T., Ihara, H., Urano, T., Takada, Y., Terakawa, S., Takada, A.: "Tissue-type plasminogen activator enhances neuronal death induced by oxygen-glucose-deprivation in culture."J. Cerebral Blood Flow and Metabolism. 21. 631-634 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ihara, H., Urano, T., Takada, A., Loskutoff, D.J.: "Induction of plasminogen activator inhibitor-1 (PAI-1) gene expression in adipocytes by thiazolidinediones."FASEB J.. 15. 1233-1235 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Urano, T., Ihara, H., Umemura, K., Suzuki, Y., Oiki, M., Akita, S., Tsukamoto, Y., Suzuki, I., Takada, A.: "The profiblinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type"J.Biol.Chem.. 276. 24690-24696 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Pawlak, R, Napioikowska-Pawlak, D, Takada, Y, Urano, T, Nagai, N, Ihara, H, Takada, A.: "The differential effect of angiotensin II and angiotensin 1-7 on norepinephrine, epinephrine, and dopamine concentrations in rat hypothalamus : the involvement of angiotensin receptors."Brain Res Bull.. 54(6). 689-694 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagai, N., Zhao, B-Q., Suzuki, Y., Ihara, H., Urano, T., Umemura, K.: "Tissue-type plasminogen activator has paradoxical roles in forcal cerebral ishemic injury by thrombotic middle cerebral artery occlusion with mild or severe photochemical damage in mice."J. Cerebral Blood Flow and Metabolism. 22. 648-651 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Pawlak, R, Nagai, N, Urano T, Napioikowska-Pawlak, D, Ihara, H., Takada, Y., Collen D., Takada, A.: "Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice."Neuroscience. 113. 995-1001 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Urano, T., Castellino, F.J., Ihara, H., Suzuki, Y., Ohta, M., Suzuki, K., Mogami, H.: "Activated protein C attenuates coagulation-associated over-expression of fibrinolytic activity by suppressing the thrombin-dependent inactivation of PAI-1."J.Thromb.Haemost.. 1. 2615-2620 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Zhao, B-Q, Ikeda Y., Ihara H., Urano T., Suzuki Y., Kondo K., Nagai N., Sato K., Umemura, K.: "Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice."Blood. Nov.20(in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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