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An approach to understand the pathophysiological role of endothelial constitutive nitric oxide synthase

Research Project

Project/Area Number 06454292
Research Category

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

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionKobe University School of Medicine

Principal Investigator

YOKOYAMA Mitsuhiro  Kobe University School of Medicine The 1st Department of Internal Medicine Professor, 医学部, 教授 (40135794)

Co-Investigator(Kenkyū-buntansha) KAWASHIMA Seinosuke  Kobe University School of Medicine The 1st Department of Internal Medicine Assos, 医学部・付属病院, 講師 (10177678)
KAWAHARA Yasuhiro  Kobe University School of Medicine The 1st Department of Internal Medicine Assos, 医学部, 講師 (80169755)
末松 正邦  神戸大学, 医学部・付属病院, 助手 (90240853)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 1995: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1994: ¥4,700,000 (Direct Cost: ¥4,700,000)
KeywordsNitric oxide synthase / Oxidized low density lipoprotein / Lysophosphatidylcholine / Atherosclerosis / Vascular endothelial cells / Protein kinase C / 低比重リボ蛋白質 / 高比重リボ蛋白質 / NO合成酵素 / プロテインキナーゼC / リゾホスファチジツコリン / 細胞内Ca^2濃度
Research Abstract

NO synthesized from L-arginine by the action of constitutive NO synthase (cNOS) in vascular endothelial cell plays an important role in the regulation of tissue perfusion. Endothelium-dependent relaxation (EDR) is markedly reduced in atherosclerotic arteries and the impairment of EDR is thought to be involved in the pathogenesis of ischemic heart disease. The purpose of the present study is to clarify the regulatory mechanisms of cNOS in vascular endothelial cells. Endothelial cNOS was phosphorylated by protein kinase C (PKC) and cAMP-dependent protein kinase. In cultured bovine aortic endothelial cells (BAECs) , phorbol esters such as TPA and PDBu inhibited NO release by A23187 as well as ATPgS through PKC activation. We employed RNase protection assay and immunoblotting to elucidate the effect of cytokine, mechanical stimuli and atherogenic lipoprotein on the expression of cNOS mRNA and protein levels in BAECs. Low concentration of ox-LDL (10mg protein/mL) or LPC (5mg/mL) upregulated cNOS mRNA levels. Furthermore, in situ hybridization and immunohistochemistry revealed that the cNOS mRNA and protein expression was normally observed in the endothelial cells overlying aortic fatty streaks in WHHL rabbits. These findings suggest that loss of EDRF activity associated with atherosclerosis is not due to an alteration of endothelial cNOS expression. In summary, ox-LDL and LPC in atherosclerotic lesion may cause endothelial dysfunction by the inhibition of receptor-mediated intracellular signaling pathway.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report

Research Products

(27 results)

All Other

All Publications (27 results)

  • [Publications] Seinosuke Kawashima: "Nitric oxide and the heart : Implication in physiological and pathological conditions in Cardiac-vascular remodeling and functional interaction." Cardiac-Vascular Remodeling and Functional Interaction. (in press). (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ken-ichi Hirata: "Activation and inhibition of nitric oxide synthase purified from cultured bovine aortic endothelial cells by phospholipids and arachidonic acids." Annals of the New York Academy of Sciences. 748. 555-558 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ken-ichi Hirata: "Inhibition of endothelial nitric oxide synthase activity by protein kinase C." Hypertension. 25. 180-183 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ken-ichi Hirata: "Low concentration of oxidized low density lipoprotein and lysophosphatidylcholine upregulate constitutive nitric oxide synthase mRNA expression in bovine aortic endothelial cells." Circulation Research. 76. 958-962 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tsuyoshi Sakoda: "Myristylation of endothelial cell nitric oxide synthase is important for extracellular releasing of nitric oxide." Molecular and Cellular Biochemistry. 152. 143-148 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kenji Kanazawa: "Endothelial constitutive nitric oxide synthase protein and mRNA were increased in atheosclerotic aorta despite of impaired endothelium-dependent vascular relaxation." American Journal of Pathology. (in press). (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ken-ichi Hirata: "Inhibition of endothelial nitric oxide synthase activity by protein kinase C." Hypertension. 25. 180-183 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ken-ichi Hirata: "Low Concentration of Oxidized Low Density Lipoprotein and Lysophosphatidylcholine Upregulate Constitutive Nitric Oxide Synthase mRNA Expression in Bovine Aortic Endothelial Cells." Circulation Research. 76. 958-962 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ken-ichi Hirata: "Activation and inhibition of nitric oxide synthase purified from cultured bovine aortic endothelial cells by phospholipids and arachidonic acids." Annals of the New York Academy of Sciences. 748. 555-558 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tsuyoshi Sakoda: "Myristylation of endothelial cell nitric oxide synthase is important for extracellular releasing of nitric oxide." Molecular and Cellular Biochemistry. 152. 143-148 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] U Ikeda: "Angiotensin II augments cytokine-stimulated nitric oxide synthesis in rat cardiac myocytes." Circulation. 92. 2683-2689 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Yoshihiro Ikeda: "Nitric oxide synthase isoform activities in kidney of Dahl salt-sensitive rats" Hypertension. 26. 1030-1034 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Seinosuke Kawashima: "Nitric oxide and the heart : Implication in physiological and pathological conditions in Cardiac-vascular remodeling and functional interaction." Cardiac-Vascular Remodeling and Functional Interaction. (in press). (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kenji Kanazawa: "Endothelial constitutive nitric oxide synthase protein and mRNA were increased in atheosclerotic aorta despite of impaired endothelium-dependent vascular relaxation." American Journal of Pathology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ken-ichi Hirata: "Inhibition of endothelial nitric oxide synthase activity by protein kinase C." Hypertension. 25. 180-183 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ken-ichi Hirata: "Low concentration of oxidized low density lipoprotein and lysophosphatidylcholine upregulate constitutive nitric oxide synthase mRNA expression in bovine aortic endothelial cells." Circulation Research. 76. 958-962 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kenji Kanazawa: "Endothelial constitutive nitric oxide synthase protein and mRNA were increased in atheosclerotic aorta despite of impaired endothelium-dependent vascular relaxation." American Journal of Pathology. (in press). (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Tsuyoshi Sakoda: "Myristylation of endothelial cell nitric oxide synthase is important for extracellular releasing of nitric oxide." Molecular and Cellular Biochemistry. 152. 143-148 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] U Ikeda: "Angiotensin II augments cytokine-stimulated nitric oxide synthesis in rat cardiac myocytes." Circulation. 92. 2683-2689 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yoshihiro Ikeda: "Nitric oxide synthase isoform activities in kidney of Dahl salt-sensitive rats." Hypertension. 26. 1030-1034 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Seinosuke Kawashima: "Cardiac-Vascular Remodeling and Functional Interaction" Nitric oxide and the heart : Implication in physiological and pathological conditions in Cardiac-vascular remodeling and functional interaction. (in press), (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ichiro Nakayama: "Angiotensin II Inhibits Cytokine-stimulated Inducible Nitric Oxide Synthase Expression in Vascular Smooth Muscle Cells" The Journal of Biological Chemistry. 269. 11628-11633 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nobutaka Inoue: "Palmitoyl-L-carnitine modifies the function of vascular endothelium." Cardiovascular Research. 71. 1410-1421 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yoichi Miwa: "Augmented receptor-mediated Ca2_+mobilization causes supersensitivity of contractile response to serotonin in atherosclerotic artery." Circulation Research. 75. 1096-1102 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ken-ichi Hirata: "Activation and inhibition of nitric oxide synthase purified from cultured bovine aoitic endothelial cells by phospholipids and arachidonic acids." Annals of the New York Academy of Sciences. 748. 555-558 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ken-ichi Hirata: "Inhibition of Endothelial Nitric Oxide Synthase Activity by protein Kinase C" Hypertension. 25. 180-185 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ken-ichi Hirata: "Low Concentration of Oxidized Low Density Lipoprotein and Lysophosphatidylcholine Upregulate Constitutive Nitric Oxide Synthase mRNA" Circulation Research. (in press). (1995)

    • Related Report
      1994 Annual Research Report

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Published: 1994-03-31   Modified: 2016-04-21  

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