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Study for the molecular mechanism of atherosclerosis

Research Project

Project/Area Number 13470146
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionOsaka University

Principal Investigator

SOBUE Kenji  Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (20112047)

Co-Investigator(Kenkyū-buntansha) HAYASHI Kenichiro  Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90238105)
西田 亙  大阪大学, 医学(系)研究科(研究院), 助手 (80271089)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2002: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2001: ¥10,300,000 (Direct Cost: ¥10,300,000)
Keywordsvascular smooth muscle cells / neointimal formation / lysophosphatidic acid / atherosclerosis / caldesmon / oxidized LDL / transcriptional machinery / MAP kinase / SRF / NKホメオ転写因子 / GATA6 / 不飽和リゾホスファチジン酸
Research Abstract

The phenotypic modulation of vascular smooth muscle cells (SMCs) from the differentiated state to the dedifferentiated one, which results in cell proliferation and migration, is a hallmark of the development and progression of atherosclerosis. Although many cytokines and growth factors have been proposed as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because proper examining systems of them have not been developed. We recently established primary culture systems for vascular SMCs in which SMCs, when cultured on laminin with insulin-like growth factor-1, show a differentiated phenotype as indicated by a spindle-like shape, ligand-induced contractility, and high levels of SMC differentiation marker gene expression.
Using our culture system, we investigated the signaling pathways affecting the vascular SMC phenotype, and found that the IGF-1-stimulated phosphoinositide 3-kinase (P13-K)/protein kinase B (PKB(Akt)) pathway plays a critical … More role in maintaining a differentiated phenotype and the coordinated activation of the extracellular-signal regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) pathways by growth factors and cytokines induces dedifferentiation. Thus, changes in the balance between the strengths of the P13-K/PKB (Akt) pathway and the ERK and p38MAPK pathways would determine the phenotype of vascular SMCs.
Using our culture system of vascular SMCs, we searched for critical dedifferentiation factors and identified that lysophosphatidic acids (LPAs) in human serum potently induce SMC dedifferentiation. Among several LPA species detected in human serum polar lipids, unsaturated LPAs were major contributors to induce vascular SMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced vascular SMC dedefferentiation also mediates through the coordinated activation of ERK and p38MAPK. Furthermore, naturally occurring unsaturated, but not saturated, LPAs strongly induced neointimal formation in rat carotid arteries in vivo.
Our study demonstrates the vascular remodeling in vivo triggered by naturally occurring unsaturated LPAs and provides a novel pathogenic animal model for atherogenesis. Less

Report

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

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Hayashi K. et al.: "Protein tyrosine phosphatase, SHP2, is a critical element of IGF-I signaling in different phenotypes of vascular smooth muscle cell"EMBO J.. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida K. et al.: "Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acids"Circulation. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Usui S.et al.: "Functional and regional compartmentation of PSD proteins, PSD-Zip45 (Homer 1c), Shank, PSD-95 and GKAP, in dendritic spines"J.Biol.Chem. 278. 10619-10628 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishida W. et al.: "A triad of serum response factor and the GATA and NK families governs the transcription of smooth and cardiac muscle genes"J.Biol.Chem. 277. 7308-7317 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamura M. et al.: "Transcriptional activation of beta-tropomyosin mediated by serum response factor and a novel Barx homologue, Barx1b, in smooth muscle cells"J.Biol.Chem. 276. 18313-18320 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayashi K. et al.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acid"Circ.Res.. 89. 251-258 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayashi K. et al.: "Protein tyrosine phosphatase, SHP2, is a critical element of IGF-1 signaling in different phenotypes of vascular smooth muscle cell"EMBO J.. (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida K. et al.: "Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acids"Circulation. (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Usui S. et al.: "Functional and regional compartmentation of PSO proteins, PSD-Zip45 (Homer 1c), Shank, PSD-95 and GKAP, in dendritic spines"J. Biol. Chem. 278. 10619-10628 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishida W. et al.: "A triad of serum response factor and the GATA and NK families governs the transcription of smooth and cardiac muscle genes"J. Biol. Chem. 277. 7308-7317 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamura M. et al.: "Transcriptional activation of beta-tropomyosin mediated by serum response factor and a novel Barx homologue, Barx1b, in smooth muscle cells"J. Biol. Chem. 276. 18313-18320 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayashi K. et al.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acid"Circ. Res.. 89. 251-258 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayashi K. et al.: "Protein tyrosine phosphatase ; SHP2, is a critical element of IGF-I signaling in different phenotypes of vascular smooth muscle cell"EMBO J.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida K. et al.: "Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acids"Circulation. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Usui S.et al.: "Functional and regional compartmentation of PSD proteins, PSD-Zip45 (Homer 1c), Shank, PSD-95 and GKAP, in dendritic spines"J.Biol.Chem.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishida W. et al.: "A triad of serum response factor and the GATA and NK families governs the transcription of smooth and cardiac muscle genes"J.Biol.Chem.. 277. 7308-7317 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamura M. et al.: "Transcriptional activation of beta-tropomyosin mediated by serum response factor and a novel Barx homologue, Barx 1b, in smooth muscle cells"J.Biol.Chem.. 276. 18313-18320 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hayashi K. et al.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acid"Circ.Res.. 89. 251-258 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishida W. et al.: "The triad of serum response factor and GATA and NK families governs transcription 120of smooth and cardiac muscle genes"J. Biol. Chem.. 277. 7308-7317 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hayashi K. et al.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acid"Circ. Res.. 89. 251-258 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakamura M. et al.: "Transcriptional activation of b-tropomyosin mediated by serum response factor and a novel Barx Homologue, Barx1b, in smooth muscle cells"J. Biol. Chem.. 276. 18310-18320 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okabe S. et al.: "Rapid redistribution of the postsynaptic density protein PSD-Zip45 (homer 1c) and its differential regulation by NMDA receptors and calcium channels"J. Neurosci.. 21. 9561-9571 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Usui S.et al.: "Functional and regional compartmentation of PSD proteins, PSD-Zip45 (Homer 1c), Shank, PSD-95 and GKAP, in dendritic spines"J. Neurosci.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Konno D. et al.: "Isolation and characterization of postsynaptic density-enriched leucine-zipper-containing protein (PSD-Zip70)"J. Biol. Chem.. (in press). (2002)

    • Related Report
      2001 Annual Research Report

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

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