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Clarification of the mechanisms for vascular neuronal nitric oxide synthase expression

Research Project

Project/Area Number 14570096
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionUniversity of Occupational and Environmental Health

Principal Investigator

TSUTSUI Masato  University of Occupational and Environmental Health, School of Medicine, Department of Pharmacology, Associate Professor, 医学部・薬理学, 助教授 (70309962)

Co-Investigator(Kenkyū-buntansha) SHIMOKAWA Hiroaki  Kyushu University Graduate School of Medical Sciences, Department of Cardiology, Associate Professor, 大学院・医学研究院・循環器内科学, 助教授 (00235681)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsNitric oxide / Nitric oxide synthase / Blood vessel / Arteriosclerosis / Gene / Expression / Smooth muscle cell / Induction / 発言
Research Abstract

Background :
Nitric oxide (NO) has multiple important actions that contribute to the maintenance of vascular homeostasis. NO is synthesized by three different isoforms of NO synthase (NOS), all of which have been reported to be expressed in human atherosclerotic vascular lesions. Although the regulatory roles of endothelial NOS (eNOS) and inducible NOS (iNOS) on the development of atherosclerosis have been described, little is known about the role of neuronal NOS (nNOS). We recently demonstrated that nNOS also exerts important vasculoprotective effects in vivo. In this study, we examined the molecular mechanisms for vascular nNOS expression.
Methods and Results :
1.In a mouse carotid artery ligation model and a rat balloon injury model, nNOS was expressed in vascular wall cells after vascular injury.
2.In cultured rat aortic smooth muscle cells, angiotensin II and lnterleukin-1β increased nNOS expression at both mRNA and protein levels. These increases in nNOS expression were inhibited by pretreatment with the nuclear factor-kappa B (NE-kB) inhibitor.
3.Platelet-derived growth factor (PDGF) also enhanced nNOS expression at both mRNA and protein levels in cultured rat aortic smooth muscle cells, which were abolished by the mitogen-activated protein (MAP) kinase (MEK) inhibitor (PD98059/U0126) and by gene transfer of dominant negative type of MEK. Importantly, gene transfer of wild-type of MEK itself elicited nNOS induction in the absence of PDGF in the cells.
Conclusions :
We were able to demonstrate that nNOS is up-regulated in vascular lesions after vascular injury, that nNOS is induced in vascular smooth muscle cells by inflammatory/proliferative stimuli, such as angiotensin II, interleukin-1β, or PDGF, and that the NE-kB and MAP kinase pathways play important roles in the vascular nNOS induction. Our findings provide a novel concept that nNOS is subject to expressional regulation in the vascular system, while it is constitutively expressed in the nervous system.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Morishita T, et al.: "Vasculoprotective roles of neuronal nitric oxide synthase"FASEB J. 10. 1096/fj.02-0155fje (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sudo O, et al.: "Long-term treatment with N^ω-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice"Circulation. 106. 1729-1735 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Morishita T, et al.: "Long-term treatment with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease"J Pharmacol Sci. 88. 100-107 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hara K, et al.: "Up-regulation of noradrenaline transporter in response to prolonged exposure to ketamine"Naunyn-Schmiedeberg's Arch Pharmacol. 365. 406-412 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shibuya I, et al.: "Regulation of catecholamine synthesis by leptin"Ann NY Acad Sci. 971. 1-6 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagai Y, et al.: "Plasma level of homocysteine is inversely associated with the development of collateral circulation in patients with single vessel coronary artery disease"Circ J. 66. 158-162 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ioka T, et al.: "Association between plasma lipoprotein(a) and endothelial dysfunction in normocholesterolemic and non-diabetic patients with angiographically normal coronary"Circ J. 66. 267-271 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobayashi K, et al.: "Vasospastic angina in a 16-year-old female : report of the youngest female patient and review of the literature"Circ J. 67. 467-469 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawada Y, et al.: "Stimulation of catecholamine synthesis by orexin-A in bovine adrenal medullary cells through orexin receptor 1"Biochem Pharmacol. 66. 141-147 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Toyohira Y, et al.: "Inhibition of the noradrenaline transporter function in cultured bovine adrenal medullary cells by bisphenol A"Biochem Pharmacol. 65. 2049-2054 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yanagihara Y, et al.: "Disturbances in catecholamine synthesis, release and reuptake by xenoestrogens"J UOEH. 25. 169-179 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsutsui M: "Neuronal nitric oxide synthase as a novel anti-atherogenic factor"J Atheroscler Thromb. 11. 41-48 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horiuchi M, et al.: "Upregulation of vascular extracellular superoxide dismutase in patients with acute coronary syndromes"Arterioscler Thromb Vasc Biol. 24. 106-111 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ueno S, et al.: "Sites of positive allosteric modulation of neurosteroids on ionotropic gamma-aminobutyric acid receptor subunits"FEBS lett. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 筒井正人, 他: "一酸化窒素合成酵素の構造と機能"蛋白質 核酸 酵素. 47. 2024-2031 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 筒井正人, 他: "RA系阻害薬と臓器保護作用"Pharma Medica. 20. 95-104 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 柳原延章, 他: "内分泌攪乱物質のカテコールアミン動態への影響"脳の科学. 25. 1149-1154 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 筒井正人, 他: "iNOSの遺伝子、産生調節機構、生理活性"日本臨床. (未定). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Morishita T, Tsutsui M, Shimokawa H, Horiuchi M, Tanimoto A, Suda O, Tasaki H, Huang PL, Sasaguri Y, Yanagihara N, Nakashima Y.: "Vasculoprotective roles of neuronal nitric oxide synthase."FASEB J.. 10.1096/fj.02-0155fje (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suda O, Tsutsui M, Morishita T, Tanimoto A, Horiuchi M, Tasaki H, Huang PL, Sasaguri Y, Yanagihara N, Nakashima Y.: "Long-term treatment with N^ω-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice."Circulation.. 106. 1729-1735 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Morishita T, Tsutsui M, Shimokawa H, Tasaki H, Suda O, Kobayashi K, Horiuchi M, Okuda H, Tsuda Y, Yanagihara N, Nakashima Y.: "Long-term treatment with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease."J.Pharmacol.Sci.. 88. 100-107 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hara K, Minami K, Ueno S, Toyohira Y, Tsutsui M, Shigematsu A, Yanagihara N.: "Up-regulation of noradrenaline transporter in response to prolonged exposure to ketamine."Naunyn-Schmiedeberg's Arch Pharmacol.. 365. 406-412 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shibuya I, Utsunomiya K, Toyohira Y, Ueno S, Tsutsui M, Cheah TB, Ueta Y, Izumi F, Yanagihara N.: "Regulation of catecholamine synthesis by leptin."Ann NY Acad Sci.. 971. 1-6 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagai Y, Tasaki H, Miyamoto M, Nihei S, Kobayashi K, Yamashita K, Tsutsui M, Kouzuma R, Okazaki M, Nakashima Y.: "Plasma level of homocysteine is inversely associated with the development of collateral circulation in patients with single vessel coronary artery disease."Circ J.. 66. 158-162 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ioka T, Tasaki H, Yashiro A, Yamashita K, Ozumi K, Tsutsui M, Kouzuma R, Okazaki M, Nakashima Y.: "Association between plasma lipoprotein(a) and endothelial dysfunction in normocholesterolemic and non-diabetic patients with angiographically normal coronary arteries."Circ J.. 66. 267-271 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobayashi K, Kouzuma R, Tsutsui M, Okazaki M, Tasaki H, Nakashima Y.: "Vasospastic angina in a 16-year-old female : report of the youngest female patient and review of the literature."Circ J.. 67. 467-469 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawada Y, Ueno S, Asayama K, Tsutsui M, Utsunomiya K, Toyohira Y, Morisada N, Tanaka K, Shirahata A, Yanagihara Y.: "Stimulation of catecholamine synthesis by orexin-A in bovine adrenal medullary cells through orexin receptor 1."Biochem Pharmacol.. 66. 141-147 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Toyohira Y, Utsunomiya K, Ueno S, Minami, K.Uezono, Y.Yoshimura R, Tsutsui M, Izumi F, Yanagihara Y.: "Inhibition of the noradrenaline transporter function in cultured bovine adrenal medullary cells by bisphenol A."Biochem Pharmacol.. 65. 2049-2054 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yanagihara Y, Toyohira Y, Tanaka K, Ueno S., Tsutsui M.: "Disturbances in catecholamine synthesis, release and reuptake by xenoestrogens."J UOEH.. 25. 169-179 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsutsui M.: "Neuronal nitric oxide synthase as a novel anti-atherogenic factor."J Atheroscler Thromb.. 11. 41-48 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horiuchi M, Tsutsui M, Tasaki H, Morishita T, Suda O, Nakata S, Nihei S, Miyamoto M, Kouzuma R, Okazaki M, Yanagihara N, Adachi T, Nakashima Y.: "Upregulation of vascular extracellular superoxide dismutase in patients with acute coronary syndromes."Arterioscler Thromb Vasc Biol.. 24. 106-111 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ueno S, Tsutsui M, Toyohira Y, Minami K, Yanagihara N.: "Sites of positive allosteric modulation of neurosteroids on ionotropic gamma-aminobutyric acid receptor subunits."FEBS lett.. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsutsui M, et al.: "Neuronal nitric oxide synthase as a novel antiatherogenic factor"Journal of Atherosclerosis and Thrombosis. 未定. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Horiuchi M, et al.: "Upregulation of vascular extracellular superoxide dismutase in patients with acute coronary syndromes"Arteriosclerosis Thrombosis and Vascular Biology. 24. 106-111 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobayashi K, et al.: "Vasospastic angina in a 16-year-old female"Circulation Journal. 67. 467-469 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 筒井正人, 他: "iNOSの遺伝子、産生調節機構、生理活性"日本臨床. 未定. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Morishita T, et al.: "Vasculoprotective roles of neuronal nitric oxide synthase"FASEB J. 10. 1096/fj.02-0155fje (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suda O, et al.: "Long-term treatment with N^ω-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice"Circulation. 106. 1729-1735 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 筒井正人 他: "一酸化窒素合成酵素の構造と機能"蛋白質 核酸 酵素. 47. 2024-2031 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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