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Elucidation of MMP-12 functions in atherosclerosis using transgenic rabbit models

Research Project

Project/Area Number 13470046
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Human pathology
Research Institution佐賀医科大学

Principal Investigator

WATANABE Teruo  Saga University, VICE PRESIDENT, 副学長 (40037396)

Co-Investigator(Kenkyū-buntansha) 北嶋 修司  佐賀大学, 総合分析実験センター, 助手 (70284643)
MORIMOTO Masatoshi  Saga University, Analytical Research Center For Experimental Sciences, 総合分析実験センター, 助教授 (90136482)
FAN Jianglin  University of Tsukuba, Institute of Basic medical sciences, Associate Professor, 基礎医学系, 助教授 (60272192)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 2002: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 2001: ¥4,700,000 (Direct Cost: ¥4,700,000)
Keywordstransgene / animal model / transgenic rabbit / extracellular matrix / MMPs / atherosclerosis / inflammation / hyperlipidemia / 細胞外質
Research Abstract

Increased matrix metalloproteinase-12 (M1VIP-l2) has been implicated in atherosclerosis and many other inflammatory processes. To define MMP-12 functions in viva, we generated transgenic rabbits that expressed human MMP-12 gene under the control of a macrophage-specific promoter, the human scavenger receptor promoter. Two transgenic founder rabbits were found n have human MMP-12 transgene integration by Southern blot analysis. hMMP-12 mRNA was expressed in peritoneal and alveolar macrophages, and in tissues enriched in macrophages in transgenic rabbits. High levels of hMMP-12 protein were detected in the conditioned media of cultured peritoneal and alveolar macrophages from transgenic rabbits. Zymography showed that hMMP-12 secreted from macrophages possessed enzymatic activity toward β-casein. To evaluate the expression of hMMP-12 in inflammatory sites, we used carrageenan-induced granulomas as an in vivo model for tissue macrophages and foam cells. Granuloma size in transgenic rabbits was significantly increased compared to that in control rabbits, and histological examination revealed that granulomas of transgenic rabbits were enriched in macrophages associated with increased hMMP-l2 expression. We believe that this transgenic rabbit model with increased expression of hMJvlP-12 may become a useful model for further mechanistic studies of MMP-12 in inflammatory diseases and cancer invasion, it is also an ideal model for testing the in vivo action of IMP-12 inhibitors.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] Wu, L.et al.: "Matrix metalloproteinase-12 gene expression in human vascular smooth muscle cells."Genes Cells. 8. 225-234 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fan, J.et al.: "Transgenic rabbits as therapeutic protein bioreactors and human disease models."Pharmacol Ther. 99. 261-282 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Koike, T.et al.: "Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity."J Biol Chem. 279. 7521-7529 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fan, J.et al.: "Macrophage-specific overexpression of human matrix metalloproteinase-12 in transgenic rabbits."Transgenic Res. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ichikawa, T.et al.: "Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis."Lab Invest. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Liu, M.et al.: "Increased expression of human matrix metalloproteinase-12 in human rheumatoid arthritis."Arthritis Rheum. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Wu, L.et al.: "Matrix metalloproteinase-12 gene exp ression in human vascular smooth muscle cells."Gene Cells. 8. 225-234 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fan, J.et al.: "Transgenic rabbits as therapeutic protein bioreactors and human disease models."Pharmacol Ther. 99. 261-282 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Koike, T. et al.: "Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity."J Biol Chem. 7521-7529 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fan, J.et al.: "Macrophage-specific overexpression of human matrix metalloproteinase-12 in transgenic rabbits."Transgenic Res. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ichikawa, T. et al.: "Overexpression of lipoprotein li ease In transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis."Lab Invest. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Liu, M.etal.: "Increased expression of human matri x metalloproteinase-12 in human rheumatoid arthritis"Arthritis Rheum. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Wu, L.: "Matrix metalloproteinase-12 gene expression in human vascular smooth muscle cells."Genes Cells. 8. 225-234 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shiomi, M.: "Development of an animal model for spontaneous myocardial infarction (WHHLMI rabbit)."Arterioscler Thromb Vasc Biol. 23. 1239-1244 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fan, J.: "Transgenic rabbits as therapeutic protein bioreactors and human disease models."Pharmacol Ther. 99. 261-282 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koike, T.: "Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity."J Biol Chem. 279. 7521-7529 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fan, J.: "Macrophage-specific overexpression of human matrix metalloproteinase-12 in transgenic rabbits."Transgenic Res. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ichikawa, T.: "Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis."Lab Invest. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ichikawa, T., Shimoyamada, H., Unoki, H., Sun, H., Shikama, T., Watanabe, T., Fan, J.: "Lipoprotein(a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo(a) transgenic rabbits"Am J. Pathol.. 160. 227-236 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Koike T, Deng H, Unoki H, Wang X, Kitajima S, Watanabe T, Fan J.: "Increased expression of lipoprotein lipase in transgenic rabbits does not lead to abnormalities in muscles and heart"Muscle & Nerve. 26. 823-827 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sun H, Usui S, Shiomi M, Watanabe T, Fan J.: "A rapid PCR method of genotyping LDL receptor mutations in WHHL rabbits"J. Atheroscl. Thromb.. 9. 145-148 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimoyamada H, Fan J, Watanabe T, Nagata, M: "Accelerated atherosclerosis with apolipoprotein(a) and oxidized low-density lipoprotein deposition in acute rejection of transplanted kidney : analogous to atherosclerosis"Clin Transplant. 16(Suppl.8). 35-39 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sun H, Unoki H, Wang X, Liang J, Ichikawa T, Shiomi M, Marcovina SM, Watanabe T, Fan J.: "Lipoprotein(a) enhances advanced atherosclerosis and vascular calcification in WHHL transgenic rabbits expressing human apolipoprotein(a)"J. Biol. Chem.. 277. 47486-47492 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fan J, Watanabe T.: "Transgenic rabbits as bioreactors and human disease experimental models"Pharmacol. Therapeut.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ichikawa, T., Shimoyamada, H., Unoki, H., Sun, H., Shikama, T., Watanahe, T., Fan, J.: "Lipoprotein(a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo(a)transgenic rabbits"Am J. Pathol.. 160. 227-236 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fan, J., Unoki, H., Kojima, N., Sun, H., Shimoyamada, H., Watanabe, T.: "Overexpression of lipoprotein lipase in transgenic rabbits inhibits diet-induced hypercholesterolemia and atherosclerosis"J. Biol. Chem.. 276. 40071-40079 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fan, J., Sun, H., Unoki, H., Shiomi, M., Watanabe, T.: "Enhanced atherosclerosis in Lp(a) WHHL transgenic rabbits"Ann New York Acad. Sci.. 947. 362-365 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fan, J., Shimoyamada, H., Sun, H., Marcovina, S., Watanabe, T.: "Transgenic rabbits expressing human apolipoprotein(a) develop enhanced atherosclerotic lesions in response to a cholesterol-rich diet"Arterioscl. Thromb. Vascul. Biol.. 21. 88-94 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wu, L., Tanimoto, A., Murata, Y., Fan, J., Sasaguri, Y.Watanabe, T.: "Induction of human metalloproteinase-12 gene transcritional activity by GM-CSF requires the AP-1 binding site in human U937 monocytic cells"Biochem. Biophys. Res. Commun.. 285. 300-307 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Iwasa, S., Fan, J., Miyauchi, T., Watanabe, T.: "Blokade of endothelin receptors reduces diet-induced hypercho1esterolemia and atherosclerosis in apoE-deficient mice"Pathobiology. 69. 1-10 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 長井 良憲: "LPS認識、応答におけるMD蛋白の役割"第31回日本免疫学会総会誌. 31. 320 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 常吉 直子: "血管内皮プロテインCレセプター(EPCR)とトロンボモジュリン(TM)の会合"生化学. 73. 787 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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