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AMP活性化タンパクキナーゼの抗動脈硬化作用と血管新生作用の検討

Research Project

Project/Area Number 17659229
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionThe University of Tokyo

Principal Investigator

平田 恭信  東京大学, 医学部附属病院, 助教授 (70167609)

Co-Investigator(Kenkyū-buntansha) 鈴木 越  東京大学, 医学部附属病院, 助手 (40313134)
佐田 政隆  東京大学, 医学部附属病院, 助教授 (80345214)
長田 太助  東京大学, 医学部附属病院, 助手 (40393194)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsAMP / キナーゼ / 動脈硬化 / 血管新生
Research Abstract

近年アディポサイトカインの心血管保護的な働きが明らかになってきた。その代表格であるアディポネクチンの作用機序のうち一部は、AMP活性化タンパクキナーゼ(AMPK)を介する。我々はその分子機序を明らかにしてきた。以前、低酸素条件下で活性化されるAMPKがAkt活性をバックアップし、Ser1177リン酸化を介して内皮型NO合成酵素(eNOS)活性化することを明らかにした。さらに、TNF-αやaldosterone(Aldo)により活性化され、血管炎症性変化を惹起するNF-kBの活性がAMPKにより抑制されることを示した。κB binding siteを有するプロモーター下流にルシフェラーゼ(luc)cDNAをもつプラスミドを、ネオマイシン耐性遺伝子発現プラスミドと共にラット血管内皮細胞へco-transfectionし、恒常的に発現する細胞(NFkB-EC)を選択した。Aldoで同細胞を刺激してluc活性を測定し、AldoによるNF-κB活性化について、対照群と比較検討した。Aldo刺激により有意にluc活性が上昇したが、mineralocorticoid receptor(MR)拮抗薬eplerenoneおよびNAD(P)H oxidase阻害薬diphenylene iodiniumの前処置により有意に抑制された。またconstitutively-active AMPK, catalaseおよびsuperoxide dismutase発現adenovirusを用いてそれぞれをNFkB-ECに過剰発現させたところ、luc活性は有意に抑制された。AldoはMRを介しNAD(P)H oxidaseの活性を上昇させ、活性酸素種(ROS)産生充進、NF-κB活性上昇を惹起させるが、AMPKはそれを有意に抑制した。現在その分子機序を解析中である。

Report

(2 results)
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • Research Products

    (13 results)

All 2007 2006 2005

All Journal Article (12 results) Book (1 results)

  • [Journal Article] A synthetic small molecule, ONO-1301, enhances endogenous growth factor expression and augments angiogenesis in ischemic heart2007

    • Author(s)
      Nakamura K, Hirata Y et al.
    • Journal Title

      Clin Sci (Lond) (In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Diverse Contribution of Bone Marrow-Derived Cells to Vascular Remodeling Associated With Pulmonary Arterial Hypertension and Arterial Neointimal Formation2007

    • Author(s)
      Sahara M, Hirata Y et al.
    • Journal Title

      Circulation 115・4

      Pages: 509-517

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Ghrelin improves renal function in mice with ischemic acute renal failure2006

    • Author(s)
      Takeda R, Hirata Y et al.
    • Journal Title

      J Am Soc Nephrol 17・1

      Pages: 113-121

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity2006

    • Author(s)
      Nagata D, Hirata Y et al.
    • Journal Title

      Hypertension 48・1

      Pages: 165-171

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effects of adrenomedullin on acute ischemia-induced collateral development and mobilization of bone marrow-derived cells2006

    • Author(s)
      Abe M, Hirata Y et al.
    • Journal Title

      Clin Sci (Lond) 111・6

      Pages: 381-387

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease2006

    • Author(s)
      Kamijo A, Hirata Y et al.
    • Journal Title

      Mol Cell Biochem 284・1-2

      Pages: 175-182

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Ghrelin improves renal function in mice with ischemic acute renal failure.2006

    • Author(s)
      Takeda R, Hirata Y et al.
    • Journal Title

      J Am Soc Nephrol 17・1

      Pages: 113-121

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Age-associated aortic stenosis in apolipoprotein E-deficient mice.2005

    • Author(s)
      Tanaka K, Hirata Y et al.
    • Journal Title

      J Am Coll Cardiol 46・1

      Pages: 134-141

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Hemodynamic and hormonal responses to a short-term low-intensity resistance exercise with the reduction of muscle blood flow.2005

    • Author(s)
      Takano H, Hirata Y et al.
    • Journal Title

      Eur J Appl Physiol 95・1

      Pages: 65-73

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Highly sensitive near-infrared fluorescence probes for nitric oxide and their application to isolated organs.2005

    • Author(s)
      Sasaki E, Hirata Y et al.
    • Journal Title

      J Am Chem Soc 127・11

      Pages: 3684-3685

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Blockade of endogenous cytokines mitigates neointimal formation in obese zucker rats.2005

    • Author(s)
      Takeda R, Hirata Y et al.
    • Journal Title

      Circulation 111・11

      Pages: 1398-1406

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Endothelial Dysfunction and Hypercontractility of Vascular Myocytes Are Ameliorated by Fluvastatin in Obese Zucker Rats2005

    • Author(s)
      Nishimatsu H, Hirata Y et al.
    • Journal Title

      Am J Physiol Heart Circ Physiol 288・4

    • Related Report
      2005 Annual Research Report
  • [Book] 血管内皮細胞をめぐる疾患2007

    • Author(s)
      平田恭信
    • Total Pages
      194
    • Publisher
      真興交易出版
    • Related Report
      2006 Annual Research Report

URL: 

Published: 2005-04-01   Modified: 2016-04-21  

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