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Experimental and Clinical Studies on the Significance of Endothelium-Derived Hyperpolarizing Factor (EDHF)

Research Project

Project/Area Number 16209027
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionTohoku University (2005-2006)
Kyushu University (2004)

Principal Investigator

SHIMOKAWA Hiroaki  Tohoku University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (00235681)

Co-Investigator(Kenkyū-buntansha) TAKESHIGE Kouichirou  Kyushu University, Faculty of Medical Sciences, Professor, 大学院医学研究院, 教授 (10037450)
UTSUMI Hideo  Kyushu University, Faculty of Pharmaceutical Sciences, Professor, 大学院薬学研究院, 教授 (20101694)
AKAIKE Takaaki  Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Associate Professcr, 大学院医学薬学研究部, 助教授 (20231798)
IBAYASHI Setsurou  Kyushu University, Faculty of Medical Sciences, Associate Professor, 大学院医学研究院, 助教授 (40213201)
HIROOKA Yoshitaka  Kyushu University, Hospital, Lectarer, 病院・講師 (90284497)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥47,970,000 (Direct Cost: ¥36,900,000、Indirect Cost: ¥11,070,000)
Fiscal Year 2006: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2005: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2004: ¥20,670,000 (Direct Cost: ¥15,900,000、Indirect Cost: ¥4,770,000)
KeywordsEndothelium-derived relaxing factors / Endothelium-derived hyperpolarizing factor / Hydrogen peroxide / Nitric oxide / Atherosclerosis / Cardiovascular diseases / Rho-kinase / Microcirculation / 内皮由来過分極因子(EDHF) / 内皮由来弛緩因子 / 内皮型NO合成酵素(eNOS) / NOS欠損マウス / eNOS欠損マウス
Research Abstract

1.Role of Endothelial NO synthases system in the production of EDHF/H_2_O2
(1)We have demonstrated that endothelial Cu, Zn-SOD plays an important role in the synthesis of EDHF/H_2O_2 not only in animals but also in humans.
(2)We have demonstrated that long-term inhibition of Rho-kinase, which down-regulates eNOS, ameliorates endothelial function in various animal models of cardiovascular diseases.
(3)We have demonstrated that EDHF/H_2O_2 is involved in the effects of ACE inhibitors.
(4)We have developed mice lacking all NO synthases. Those mice showed impaired survival with hypertension and myocardial infarction.
(5)In those triply NOSs-KO mice, EDHF responses were abolished, demonstrating the importance of endothelial NOSs system in the synthesis of EDHF/H_2O_2.
2.Mechanisms of Physiological and Pathological H_2O_2 Synthesis
(1)We were able to demonstrate that endothelial cells release H_2O_2 and NO at p.M order and that the two factors interact synergistically to maintain coronary flow in dogs in vivo.
(2)We have demonstrated that other endothelial oxidases system (e.g.NADPH) are not involved in the EDHF/H_2O_2 responses.
3.In vivo imaging of H_2O_2
We were able to demonstrate endothelial production of H_2O_2 using DCF fluorescence imaging in vivo.
4.Role of EDHF/H_2O_2 in animals
We have demonstrated that EDHF/H_2O_2 plays an important protective role in myocardial ischemia/reperfusion and metabolic coronary vasodilatation as well.
5.Role of EDHF/H_2O_2 in humans
(1)We have demonstrated that in cultured vascular smooth muscle cells from human coronary arteries, estrogen down-regulates while nicotine up-regulates Rho-kinase.
(2)We have demonstrated that selective Rho-kinase inhibitors acutely reduces pulmonary vascular resistance without systemic hemodynamic effects in patients with pulmonary hypertension.

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (29 results)

All 2007 2006 2005 2004

All Journal Article (27 results) Book (2 results)

  • [Journal Article] Important role of hydrogen peroxide in pacing-induced metabolic coronary vasodilatation in dogs in vivo.2007

    • Author(s)
      Yada T, Shimokawa H, et al.
    • Journal Title

      Journal of the American College of Cardiolgy (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Important role of hydrogen peroxide in pacing-induced metabolic coronary vasodilatation in dogs in vivo.2007

    • Author(s)
      Yada T, Shimokawa H, Hiramatsu O, Shinozaki Y, Mori H, Goto M, Ogasawara Y, Kajiya F.
    • Journal Title

      J Am Coll Cardiol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cardioprotective role of hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo.2006

    • Author(s)
      Yada T, Shimokawa H, et al.
    • Journal Title

      American Journal of Physiology 291

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cardioprotective role of hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo.2006

    • Author(s)
      Yada T, Shimokawa H, Hiramatsu O, Shinozaki Y, Mori H, Kiyooka T, Goto M, Ogasawara Y, Kajiya F.
    • Journal Title

      Am J Physiol. 291

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Important role of endogenous erythropoietin system to recruit endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice.2006

    • Author(s)
      Satoh K, et al.
    • Journal Title

      Circulation 113

      Pages: 1442-1450

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Cardioprotective role of hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo.2006

    • Author(s)
      Yada T, et al.
    • Journal Title

      American Journal of Physiology 291

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice.2006

    • Author(s)
      Nakano M, et al.
    • Journal Title

      Circulation Research 100

      Pages: 662-669

    • Related Report
      2006 Annual Research Report
  • [Journal Article] NO/活性酸素による血管シグナル伝達機構2006

    • Author(s)
      森川敬子, 下川宏明
    • Journal Title

      細胞工学 25

      Pages: 166-169

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 内皮由来過分極因子と内皮機能障害2006

    • Author(s)
      高木文, 下川宏明
    • Journal Title

      日本臨床 64

      Pages: 240-243

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. (Review)2005

    • Author(s)
      Shimokawa H, Morikawa K
    • Journal Title

      Journal of Molecular and Cellular Cardiology 39

      Pages: 725-732

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms.2005

    • Author(s)
      Morishita T, Tsutsui M, Shimokawa H. et al.
    • Journal Title

      Proceedings of the National Academy of Sciences, USA 102

      Pages: 10616-10621

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin converting enzyme inhibitor on EDHF-mediated responses in mice.2005

    • Author(s)
      Fujiki T, Shimokawa H, et al.
    • Journal Title

      Arteriosclerosis, Thrombosis, and Vascular Biology 25

      Pages: 766-771

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans.2005

    • Author(s)
      Shimokawa H, Morikawa K.
    • Journal Title

      J Mol Cell Cardiol.(Review) 3 9

      Pages: 725-732

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms.2005

    • Author(s)
      Morishita T, Tsutsui M, Shimokawa H, Sabanai K, Tasaki H, Suda 0, Nakata S, Tanimoto A, Wang K-Y, Ueta Y, Sasaguri Y, Nakashima Y, Yanagihara N.
    • Journal Title

      Proc Nat'l Acad Sci USA. 102

      Pages: 10616-10621

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin converting enzyme inhibitor on EDHF-mediated responses in mice.2005

    • Author(s)
      Fujiki T, Shimokawa H, Morikawa K, Kubota H, Hatanakla M, Talukder MAH, Matoba T, Takleshita A, Sunagawa K.
    • Journal Title

      Arterioscler Thromb Vase Biol. 25

      Pages: 766-771

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo -A possible link between stress and coronary vasospasm-.2005

    • Author(s)
      Hizume T, et al.
    • Journal Title

      Circulation Research 99

      Pages: 767-775

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin converting enzyme inhibitor on EDHF-mediated responses in mice.2005

    • Author(s)
      Fujiki T, Shimokawa H, et al.
    • Journal Title

      Arteriosclrosis, Thrombosis, and Vascular Biology 25

      Pages: 766-771

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Influence of diabetes, hypercholesterolemia, and their combination on EDHF-mediated responses in mice.2005

    • Author(s)
      Morikawa K, Shimokawa H, et al.
    • Journal Title

      Journal of Cardiovascular Pharmacology 45

      Pages: 485-490

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms.2005

    • Author(s)
      Morishita T, Tsutsui M, Shimokawa H, et al.
    • Journal Title

      Proceedings of National Academy Science USA 102

      Pages: 10616-10621

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. (Review)2005

    • Author(s)
      Shimokawa H, Morikawa K.
    • Journal Title

      Journal of Molecular and Cellular Cardiology. 39

      Pages: 725-732

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin converting enzyme inhibitor on EDHF-mediated responses in mice.2005

    • Author(s)
      Fujiki T, Shimokawa H, et al.
    • Journal Title

      Arteriosclrosis, Thrombosis, and Vascular Biology (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Influence of diabetes, hypercholesterolemia, and their combination on EDHF-mediated responses in mice.2005

    • Author(s)
      Morikawa K, Shimokawa H, et al.
    • Journal Title

      Journal of Cardiovascular Pharmacology (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Important role of superoxide dismutase in EDHF-mediated responses of human mesenteric arteries.2004

    • Author(s)
      Morikawa K, Shimokawa H.
    • Journal Title

      Journal of Cardiovascular Pharmacology 44

      Pages: 552-556

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Important role of superoxide dismutase in EDHF-mediated responses of human mesenteric arteries.2004

    • Author(s)
      Morikawa K, Matoba T, Kubota H, Hatanaka M, Fujiki T, Takahashi S, Shimokawa H.
    • Journal Title

      J Cardiovasc Pharmacol. 44

      Pages: 552-556

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Upregulated neuronal nitric oxide synthase compensates coronary flow response to bradykinin in endothelial nitric oxide-deficient mice.2004

    • Author(s)
      Talukder MAH, Shimokawa H, et al.
    • Journal Title

      Journal of Cardiovascular Pharmacology 44

      Pages: 437-445

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Endothelial nitric oxide synthase-independent effect of an ACE inhibitor on coronary flow response to bradykinin in mice.2004

    • Author(s)
      Talukder MAH, Shimokawa H, et al.
    • Journal Title

      Journal of Cardiovascular Pharmacology 44

      Pages: 557-563

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Important role of superoxide dismutase in EDHF-mediated responses of human mesenteric arteries2004

    • Author(s)
      Morikawa K, Shimokawa H, et al.
    • Journal Title

      Journal of Cardiovascular Pharmacology 44

      Pages: 552-556

    • Related Report
      2004 Annual Research Report
  • [Book] Annual Review循環器2007(山口 徹、高本真一、中沢 誠、小室一成(編))(EDHF.)2007

    • Author(s)
      高木文, 下川宏明
    • Publisher
      中外医学社
    • Related Report
      2006 Annual Research Report
  • [Book] 内科学(第9版) 欠陥の収縮弛緩と血圧調節機構2006

    • Author(s)
      下川宏明
    • Publisher
      朝倉書店(印刷中)
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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