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Establishment of A New Strategy for the Treatment of Atherosclerosis by Activating Reverse Cholesterol Transport

Research Project

Project/Area Number 11557054
Research Category

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

Allocation TypeSingle-year Grants
Section展開研究
Research Field Circulatory organs internal medicine
Research InstitutionOsaka University Graduate School of Medicine

Principal Investigator

SAKAI Naohiko  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (80294073)

Co-Investigator(Kenkyū-buntansha) HIRANO Kenichi  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手
FUNAHASHI Tohru  Osaka University Graduate School of Medicine, Lecrurer, 医学系研究科, 講師 (60243234)
YAMSHITA Shizuya  Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (60243242)
ARAGANE Katsumi  Fujirebio Inc., Researcher, 中央研究所・医薬第8研究室, 研究員
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2000: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1999: ¥6,800,000 (Direct Cost: ¥6,800,000)
KeywordsCdc42Hs / high density lipoprotein (HDL) / reverse cholesterol transport / Tangier disease / efflux / atherosclerosis / lipid transport / cDNA subtraction
Research Abstract

Cholesterol efflux (CE) is the initial and important step of reverse cholesterol transport, a major protective system against atherosclerosis. Tangier disease (TD) is a familial HDL deficiency the primary defect of which is characterized by the abnormality in CE by HDL from peripheral cells. cDNA subtraction revealed that the expression of a member of the Rho GTPase family, Cdc42Hs, was markedly decreased in both passaged fibroblasts and macrophages from patients with TD.We demonstrated that MDCK cells expressing the dominant negative form of Cdc42Hs had reduced CE, whereas those expressiong the dominant active form had increased CE, suggesting that Cdc42Hs is one of the intracellular molecules involved in CE.In addition, the FRAP (fluorescence recovery after photobleaching) revealed that the intracellular lipid transport is retarded in TD fibroblasts which is probably associated with the impaired CE.The fibroblasts from TD patients infected with recombinant adenovirus expressing dominant form of Cdc42Hs recovered the normal CE and intracellular lipid transport. Thus, the decreased expression of Cdc42Hs is demonstrated to be related to the pathophysiology of TD.The finding of the Cdc42Hs as an intracellular molecule involved in CE possibly contributes the establishment of a new strategy for the treatment of atherosclerosis by activating CE by HDL from peripheral cells, especially mcrophages.

Report

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

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Lambert G,Sakai N, et al.: "Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase deficient mice"J Biol Chem. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyaoka K,Kuwasako T, et al.: "CD36 deficiency associated with insulin resistance"Lancet. 357. 686-687 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuyama A, et al.: "Characterization and purification of a GPI-anchored type HDL-binding protein on human monocyte-derived macrophages. Biochem Biophys Res Commun"Biochem Biophys Res Commun. 272. 864-871 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hirano K, et al.: "Decreased expression of a member RhoGTPases family, Cdc42Hs, in cells from Tangier disease. -The small G protein may play a role in cholesterol efflux from the cells-"FEBS letters. 484. 275-279 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komuro R, et al.: "Tangier disease with continuously massive and longitudinal diffuse calcification in the coronary arteries.-Demonstration by the sagittal images of intravascular ultrasonography.-"Circulation. 101. 2446-2448 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamashita S, et al.: "Molecular biology and pathophysiological aspects of plasma cholesteryl ester transfer protein"Biochim Biophys Acta. 1529. 257-275 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hirano K, et al.: "Expression of human scavenger receptor class B type I in cultured human monocyte-derived macrophages and atherosclerotic lesions."Circ Res. 85. 108-116 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuyama A, et al.: "Characterization and purification of a GPI-anchored type HDL-binding protein on human monocyte-derived macrophages."Biochem Biophys Res Commun. 272. 864-871 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komuro R, et al.: "Tangier disease with continuously massive and longitudinal diffuse calcification in the coronary arteries. -Demonstration by the sagittal images of intravascular ultrasonography-"FEBS letters. 484. 275-279 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hirano K, et al.: "Decreased expression of a member RhoGTPases family, Cdc42Hs, in cells from Tangier disease. -The small G protein may play a role in cholesterol efflux from the cells-"Circulation. 101. 2446-2448 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Janabi M, et al.: "Oxidized LDL-induced NF-kB activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients."Arterioscler Thromb Vasc Biol. 20. 1953-1960 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamashita S, et al.: "Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia."Atherosclerosis. 152. 271-285 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamashita S, et al.: "Molecular biology and pathophysiological aspects of plasma cholesteryl ester transfer protein."Biochim Biophys Acta. 1529. 257-275 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyaoka K, Kuwasako T, et al.: "CD36 deficiency associated with insulin resistance."Lancet. 357. 686-687 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Lambert G, Sakai N, et al.: "Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase deficient mice."J Biol Chem. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Lambert G,Sakai N, et al.: "Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase deficient mice"J Biol Chem. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Nagano M, et al.: "A point mutation (-69 G to A) in the promoter region of cholesteryl ester transfer protein gene in Japanese hyperalphaliponroteinemic subjects"Arterioscler Thromb Vasc Biol. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Zhang Z, et a;.: "Expression of cholesteryl ester transfer protein in human atherosclerotic lesions and its implication of the reverse cholesterol transport"Atherosclerosis. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyaoka K,Kuwasako T, et al.: "CD36 deficiency associated with insulin resistance"Lancet. 357. 686-687 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hirano K, et al.: "Pros and cons of inhibiting CETP"Curr Opin Lipidol. 11. 589-594 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hirano K, et al.: "Decreased expression of a member RhoGTPases family, Cdc42Hs, in cells from Tangier disease. -The small G protein may play a role in cholesterol efflux from the cells"FEBS letter. 484. 275-279 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Komuro R et al.: "Tangier disease with continuously massive and longitudinal diffuse calcification in the coronary arteries-Demonstration by the sagittal images of intravascular ultrasonography-"Circulation. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamashita S et al.: "Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperaphalipoproteinemia"Atherosclerosis. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Hirano K et al.: "Expression of human scavenger receptor class B type I(SR-BI)in cultured human monocyte-derived macrophages and atherosclerotic lesions"Circ Res. 8. 108-116 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsuura F et al.: "Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-derived lipids and marked hypercholesterolemia.-possible pathogenesis of necrobiotic xanthogranuloma-"Atherosclerosis. 142. 355-365 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakata A et al.: "CD36, a novel receptor for oxidized low density lipoproteins, is highly expressed on lipid-laden macrophages in human atherosclerotic aorta"Arterioscler Thromb Vasc Biol. 18. 1350-1357 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsuyama A et al.: "Characterization and purification of a GPI -anchored type HDL-binding protein on human monocyte-derived macrophages"Circulation. 100(suppl.). I-330 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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