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Molecular mechanism of the signaling pathways that induce dedifferentiation of smooth muscle cells

Research Project

Project/Area Number 13670120
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionOsaka University

Principal Investigator

HAYASHI Kenichiro  Osaka Univ. Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90238105)

Co-Investigator(Kenkyū-buntansha) SOBUE Kenji  Osaka Univ. Graduatre School of Medicine, Professor, 医学系研究科, 教授 (20112047)
西田 亘  大阪大学, 医学系研究科, 助手 (80271089)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsvascular smooth muscle cells / dedifferentiation / unsaturated Iysophosphatidic acids / signal transduction / ERK / p38MAPK / atherosclerosis / 不砲和リゾフォスファチンジン酸
Research Abstract

The phenotypic modulation of vascular smooth muscle cells (SMCs) from the differentiated state to the dedifferentiated one is critical event in the development and progression of atherosclerosis. However, the critical atherogenic factors remain unclear. We established primary culture systems for visceral and vascular SMCs in which both SMCs can maintain a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level expression of SMC differentiation markers. In this study, we searched for critical SMC dedifferentiation factors using our culture systems. We found that polar lipids extracted from human serum markedly induced SMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several LPA species detected in human serum lipids, unsaturated LPAs were identified as major contributors for SMC dedifferentiation. Unsaturated (18:1) LPA, but not saturated (18:0) LPA, strongly induced vascular SMC dedifferentiation in culture and vascular remodeling consisted of neointima in rat carotid arteriesin vivo. 18:1 LPA-induced vascular SMC dedifferentiation in culture and vascular remodelingin vivo were mediated through the coordinated activation of both ERK and p38 MAPK. The neointima was mainly derived from dedifferentiated medial vascular SMCs. During 18:1 LPA-induced vascular remodeling, the phenotypic modulation of medial vascular SMCs preceded macrophage infiltration. Thus, this study demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce vascular SMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.

Report

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

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Nakamura M.: "Transcriptional activation of β-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.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids"Cir. 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] 林 謙一郎: "平滑筋細胞形質転換の分子メカニズム"細胞 The Cell. 33. 328-333 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishida W.: "A triad of SRF and the GATA and NK families governs the transcription of smooth and cardic 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] 林 謙一郎: "分化型・脱分化型血管平滑筋細胞のシグナル伝達と転写制御機構"分子心血管病. 3. 647-657 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohkawa Y.: "Calcineurin-mediated pathway involved in the differentiated phenotype of smooth muscle cells"Biochem. Biophys. Res. Commun.. 301. 78-83 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamura M.: "Transcriptional activation of β-tropomyosin mediated by serum response factor and a novel Barx homologue, Barxlb, in smooth muscle cells"J. Biol. Chem.. 276. 18313-1832 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayashi K.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids"Cir. 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.: "Molecular mechanism of phenotypic modulation of smoothmuscle cells"The Cell. 33. 328-333 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishida W.: "A triad of SRF 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] Hayashi K.: "Molecular mechanism of signal transduction and transcription in differentiated and dedifferentiated smooth muscle cells"Molecular Cardiovascular Medicine. 3. 674-657 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohkawa Y.: "Calcineurin-mediated pathway involved in the differentiated phenotype of smooth muscle cells"Biochem. Biophys. Res. Commun.. 301. 78-83 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamura M.: "Transcriptional activation of β-tropomyosin mediated by serum response factor and a novel Barx homologue, Barx1b, in smooth muscle cells"J.Biol.Chem.. 276・21. 18313-18320 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hayashi K.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophoshatidic acids"Cir.Res.. 89・3. 251-258 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] 林 謙一郎: "平滑筋細胞形質転換の分子メカニズム"細胞The Cell. 33・9. 328-333 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishida W.: "A triad of SRF and the GATA and NK families governs the transcription of smooth and cardiac muscle genes"J.Biol.Chem.. 277・9. 7308-7317 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 林 謙一郎: "分化型・脱分化型血管平滑筋細胞のシグナル伝達と転写制御機構"分子心血管病. 3・6. 647-657 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohkawa Y.: "Calcineurin-mediated pathway involved in the differentiated phenotype of smooth muscle cells"Biochem.Biophys.Res.Commun.. 301・1. 78-83 (2003)

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

    • Related Report
      2001 Annual Research Report
  • [Publications] Hayashi K: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophoshatidic acids"Cir. Res. 89. 251-258 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 林 謙一郎: "平滑筋細胞形質転換の分子メカニズム"細胞 The Cell. 33. 328-333 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nishida W: "A triad of SRF and the GATA and NK families governs the transcription of smooth and cardiac muscle genes"J. Biol. Chem.. 277. 7308-7317 (2002)

    • Related Report
      2001 Annual Research Report

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

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