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Investigation of mechanotransduction mechanism in pulmonary artery for therapeutic application of experimental pulmonary hypertension.

Research Project

Project/Area Number 14572059
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionUniversity of Shizuoka

Principal Investigator

TANABE Yoshiyuki  School of Pharmaceutical Sciences, Department of Pharmacology, Research Associate, 薬学部, 助手 (10275109)

Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsMechanical stress / Phospholipase A_2 / Prostaglandin H_2 / Pulmonary hypertension / Pulmonary artery / Integrin / Indoxam / Stretching / ホスホリパーゼA2 / エイコサノイド / PGH_2 / アラキドン酸カスケード / 内皮細胞 / プロスタグランジン / 肺癌高血圧症 / 肺高血圧症 / アンジオテンシンII / リモデリング
Research Abstract

Pathogenicity of vasculature with chronically increased hemodynamics such as hypertension and arteriosclerosis may be attributable in part to biological responses of cardiovascular tissues against mechanical stimuli. The research purpose of this study is to find a new therapeutic target for experimental pulmonary hypertension through pharmacological regulation of mechanotransduction mechanisms of pulmonary artery.
Mechanical stretching to 180% of initial muscle length produces the excessive arterial tension, which is considered to be similar degree in the pulmonary hypertension. The stretching of the pulmonary artery activates downstream signal of integrin, a putative mechanosensor; nevertheless, the stretching augments productions of prostanoids in an integrin-dependent (TXA_2 and PGF_<2α>) and independent (untransformed (ut-)PGH_2, PGE_2, and PGI_2) manner. Of these prostanoids, moreover, the ut-PGH_2 was primarily responsible for the stretch-induced contraction of the pulmonary arter … More y. Assuming that integrin-independent pathway of PG-production might be mediated by secretory phospholipase A_2 (sPLA_2), the effects of indoxam, a highly selective inhibitor for sPLA_2, on the contraction of pulmonary artery and the production of ut-PGH_2 in response to stretching were examined. In a normal rabbit pulmonary artery, indoxam preferentially inhibit the stretch-induced contraction (IC_<50>=0.513 μM), which was about 20-fold more effective than acetylcholine-induced contraction (IC_<50>=10.25 μM). Production of ut-PGH_2 was abolished by indoxam at this time. In the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PH rats), a significant increase in the steady-state mRNA level for group X sPLA_2 was observed. Indoxam (1-3 μM) completely abolished rhythmic contraction as well as concomitant production of ut-PGH_2 during the prolonged stretching, which is an aberrant character of the pulmonary artery of MCT-PH rats.
These results suggest that sPLA_2-mediated production of ut-PGH_2 causes stretch-induced contraction and/or increasing vascular tone of the pulmonary arteries in both normal and the pulmonary hypertension. Successful blockade by Indoxam of ut-PGH_2-production and contractile responses of the pulmonary arteries in both normal and diseased status suggest that sPLA_2 would become a new therapeutic target for experimental pulmonary hypertension. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (32 results)

All 2005 2004 2003 Other

All Journal Article (25 results) Publications (7 results)

  • [Journal Article] Cyclic stretching and eicosapentaenoic acid synergistically inhibit adipocyte differentiation of 3T3-L1 cells.2005

    • Author(s)
      Matsunaga Y, Tanabe Y, Nakayama K
    • Journal Title

      Journal of Pharmacological Sciences 97(suppl.I)

      Pages: 118-118

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cyclic stretching and eicosapentaenoic acid synergistically inhibit adipocyte differentiation of 3T3-L1 cells2005

    • Author(s)
      Matsunaga, Yumi, Tanabe, Yoshiyuki, Nakayama, Koichi
    • Journal Title

      Journal of Pharmacolgical Sciences 97(suppl. I)

      Pages: 118-118

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cyclic stretching and eicosapentaenoic acid synergistically inhibit adipocyte differentiation of 3T3-L1 cells.2005

    • Author(s)
      Matsunaga Y., Tanabe Y., Nakayama K.
    • Journal Title

      Journal of Pharmacological Science 97 suppl I

      Pages: 118-118

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cyclic stretching and eicosapentaenoic acid synergistically inhibit adipocyte differentiation of 3T3-L1 cells.2004

    • Author(s)
      Tanabe Y, Koga M, Saito M, Matsunaga M, Nakayama K
    • Journal Title

      Journal of Cell Science 117

      Pages: 3605-3614

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 機械的伸展刺激による脂肪細胞分化の抑制機構2004

    • Author(s)
      田辺由幸, 中山貢一
    • Journal Title

      日本薬理学雑誌 124

      Pages: 337-344

    • NAID

      10014385080

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 機械的伸展刺激による脂肪細胞分化の抑制機構2004

    • Author(s)
      田辺由幸, 中山貢一
    • Journal Title

      日本薬理学雑誌 124(補冊)

      Pages: 41-42

    • NAID

      10014385080

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanical stretch inhibits adipocyte differentiation of 3T3-L1 cells.2004

    • Author(s)
      Tanabe Y, Obara K, Ishikawa T, Nakayama K
    • Journal Title

      Journal of Pharmacological Sciences 94(suppl.I)

      Pages: 69-69

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated down-regulation of PPARγ_22004

    • Author(s)
      Tanabe, Yoshiyuki, Koga, Masaru, Saito, Maki, Matsunaga, Yumi, Nakayama, Koichi
    • Journal Title

      Journal of Cell Science 117

      Pages: 3605-3614

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanical stretching inhibits adipocyte diffenretiation of 3T3-L1 cells: the molecular Mechanism and pharmacological regulation.(Japanese)2004

    • Author(s)
      Tanabe, Yoshiyuki, Nakayama, Koichi
    • Journal Title

      Nippon Yakurigaku Zasshi 124

      Pages: 337-344

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanical stretching inhibits adipocyte differentiation of 3T3-L1 cells: the molecular mechanism and pharmacological regulation. (Japanese)2004

    • Author(s)
      Tanabe, Yoshiyuki, Nakayama, Koichi
    • Journal Title

      Nippon Yakurigaku Zasshi 124(suppl)

      Pages: 41-42

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanical stretch inhibits adipocyte differentiation of 3T3-L1 cells2004

    • Author(s)
      Tanabe, Yoshiyuki, Obara, Kazuo, Ishikawa, Tomohisa, Nakayama, Koichi
    • Journal Title

      Journal of Pharmacolgical Sciences 94(suppl. I)

      Pages: 69-69

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated down-regulation of PPARγ_2.2004

    • Author(s)
      Tanabe Y., Koga M., Saito M, Matsunaga Y, Nakayama K.
    • Journal Title

      Journal of Cell Science 117

      Pages: 3605-3614

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 機械的伸展刺激による脂肪細胞分化の抑制機構2004

    • Author(s)
      田辺由幸, 中山貢一
    • Journal Title

      日本薬理学雑誌(Folia Pharmacol.Jpn.) 124

      Pages: 337-344

    • NAID

      10014385080

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 機械的伸展刺激による脂肪細胞分化の抑制機構と薬物制御2004

    • Author(s)
      田辺由幸, 中山貢一
    • Journal Title

      日本薬理学雑誌(Folia Pharmacol.Jpn.) 124(補冊)

      Pages: 41-42

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mechanical stretch inhibits adipocyte differentiation of 3T3-L1 cells.2004

    • Author(s)
      Tanabe Y, Obara K, Ishikawa T, Nakayama K
    • Journal Title

      Journal of Pharmacological Science 94 (suppl.)

      Pages: 69-69

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Interactive role for tyrosine kinase, protein kinase C, and Rho/Rho kinase systems in the mechanotransduction of vascular smooth muscles.2003

    • Author(s)
      Nakayama K, Obara K, Tanabe Y, Saito M, Ishikawa T, Nishizawa S
    • Journal Title

      Biorheology 40

      Pages: 307-314

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Endothelium-derived prostaglandin H_2 evokes the stretch-induced contraction of rabbit pulmonary artery.2003

    • Author(s)
      Saito M, Tanabe Y, Kudo I, Nakayama K
    • Journal Title

      European Journal of Pharmacology 467

      Pages: 151-161

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] メカニカルストレスと血管反応:脳血管攣縮との類似性2003

    • Author(s)
      中山貢一, 小原一男, 田辺由幸, 石川智久, 西澤 茂, 小出昌代
    • Journal Title

      日本薬理学雑誌 122(補冊)

      Pages: 33-36

    • NAID

      10018622277

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Chronic hypoxia differentially modulates extracellular signal-regulated protein kinase pathway in right ventricle and lung tissues of mice.2003

    • Author(s)
      Kato T, Tanabe Y, Iwata H, Isobe K, Inagaki Y, Nakayama K
    • Journal Title

      Journal of Pharmacological Sciences 91(suppl.1)

      Pages: 88-88

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 20-hydroxyeicosatetraenoic acid potentiates contractile activation of canine basilar artery in response to stretch via protein kinase C alpha-mediated inhibition of calcium-activate2003

    • Author(s)
      Nakayama K, Obara K, Tanabe Y, Ishikawa T
    • Journal Title

      Molecular and Cellular Aspects of Muscle Contraction Advances in Experimental Medicine and Biology 538

      Pages: 411-416

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interactive role for tyrosine kinase, protein kinase C, and Rho/Rho kinase systems in the mechanotransduction of vascular smooth muscles2003

    • Author(s)
      Nakayama, Koichi, Obara, Kazuo, Tanabe, Yoshiyuki, Saito, Maki, Ishikawa, Tomohisa, Nishizawa, Shigeru
    • Journal Title

      Biorheology 40

      Pages: 307-314

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Endothelium-derived prostaglandin H_2 evokes the stretch-induced contraction of rabbit pulmonary artery2003

    • Author(s)
      Saito, Maki, Tanabe, Yoshiyuki, Kudo, Ichiro, Nakayama, Koichi
    • Journal Title

      European Journal of Pharmacology 467

      Pages: 151-161

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanical stress and cerebrovascular response: resemblance to cerebral vasospasm after subarachnoid hemorrhage2003

    • Author(s)
      Nakayama, Koichi, Obara, Kazuo, Tanabe, Yoshiyuki, Ishikawa, Tomohisa, Nishizawa, Shigeru, Koide Masayo
    • Journal Title

      Nippon Yakurigaku Zasshi 122(suppl)

      Pages: 33-36

    • NAID

      10018622277

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Chronic hypoxia differentially modulates extracellular signal-regulated protein kinase pathway in right ventricle and lung tissues of mice2003

    • Author(s)
      Kato, Takao, Tanabe, Yoshiyuki, Iwata, Hijiri, Isobe, Kaori, Inagaki, Yoshifumi, Nakayama, Koichi
    • Journal Title

      Journal of Pharmacolgical Sciences 91(suppl. I)

      Pages: 88-88

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 20-hydroxyeicosatetraenoic acid potentiates contractile activation of canine basilar artery in response to stretch via protein kinase C alpha-mediated inhibition of calcium-activated potassium channel2003

    • Author(s)
      Nakayama, Koichi, Obara, Kazuo, Tanabe, Yoshiyuki, Ishikawa, Tomohisa
    • Journal Title

      Advances in Experimental Medicine and Biology 538

      Pages: 411-416

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Tanabe Y, Koga M, Saito M, Matsunaga Y, Nakayama K: "Inhibition of adipocyte differentiation by mechanical streching through ERK-mediated down-regulation of PPARγ2."Journal of Cell Science. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanabe Y, Obara K, Ishikawa T, Nakayama K: "Mechanical stretch inhibits adipocyte differentiation of 3T3-L1 cells."Journal of Pharmacological Sciences. 94. 69 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中山貢一, 小原一男, 田辺由幸, 石川智久, 西澤茂, 小出昌代: "メカニカルストレスと血管反応/脳血管攣縮との類似性"日本薬理学雑誌. 122(補冊). 33-36 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saito M, Tanabe Y, Kudo I, Nakayama K: "Endothelium-derived prostaglandin H_2 evokes stretch-induced contraction of rabbit pulmonary artery"European Journal of Pharmacology. vol.467. 151-161 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato T, Tanabe Y, Iwata H, Isobe K, Inagaki, Nakayama K: "Chronic hypoxia differentially modulates extracellular signal-regulated protein kinase pathway in right ventricle and lung tissues of mice"Journal of Pharmacological Science. vol.91,Suppl.1. 88 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakayama K, Obara K, Tanabe Y, Saito M, Ishikawa T, Nishizawa S: "Interactive role of tyrosine kinase, protein kinase C, and Rho/Rho kinase systems in the mechanotransduction of vascular smooth muscles"Biorheology. vol.40. 307-314 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Obara K, Tanabe Y, Ishikawa T, Nakavama K: "Mechanotransduction of vascular smooth muscles : Rate-dependent stretch-induced protein phosphorylations and contractile activation"Japanese Journal of Pharmacology. vol.88,Suppl.1. 10 (2002)

    • Related Report
      2002 Annual Research Report

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

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