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Elucidation of the novel signaling pathway of vimentin-mediated abnormal vascular smooth muscle contraction

Research Project

Project/Area Number 20K07261
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48020:Physiology-related
Research InstitutionYamaguchi University

Principal Investigator

Kishi Hiroko  山口大学, 大学院医学系研究科, 准教授 (40359899)

Co-Investigator(Kenkyū-buntansha) 小林 誠  山口大学, 医学部, 教授(特命) (80225515)
張 影  山口大学, 大学院医学系研究科, 講師 (10711260)
森田 知佳  山口大学, 大学院医学系研究科, 助教 (70763796)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords血管平滑筋 / 異常収縮 / ビメンチン / カルパイン / Rhoキナーゼ
Outline of Research at the Start

血管攣縮は、心筋梗塞、脳血管障害などの急性発症で致死的な疾病を引き起こす。研究代表者らは、生体で血管攣縮を引き起こす血管平滑筋異常収縮のシグナル伝達経路として、SPC/Fyn/ROK経路を見出し、更に、Fyn下流の新規血管平滑筋異常収縮シグナル分子の一つとしてビメンチンを同定した。異常収縮刺激時にビメンチンはカルパインによって切断され、更に、血管平滑筋異常収縮がカルパイン阻害薬により抑制される事から、『構造蛋白として知られるビメンチンが、真に、カルパイン活性依存的に血管平滑筋異常収縮のシグナル分子として機能するのか?』という学術的「問い」に至り、これを解明するため本研究を行う。

Outline of Final Research Achievements

Abnormal vascular smooth muscle contraction induces acute and fetal diseases such as myocardial infarction and cerebral ischemia. We previously identified sphingosylphosphorylcholine/Fyn/Rho kinase (ROK) pathway as novel and specific signaling pathway to mediate abnormal vascular smooth muscle contraction. Furthermore, we identified vimentin as a downstream signaling molecule of Fyn and found that vimentin was cleaved by calpain protease upon abnormal vascular smooth muscle contraction. The overexpression of vimentin fragment induced ROK activation and myosin light chain phosphorylation in vascular smooth muscle cells, suggesting that vimentin fragment facilitate the signal transduction which mediates abnormal vascular smooth muscle contraction.

Academic Significance and Societal Importance of the Research Achievements

血管平滑筋異常収縮は、生体において血管攣縮を引き起こす病的な収縮であり、細胞質カルシウム濃度の上昇を必要としないCa2+非依存性の収縮である。従来、Rhoキナーゼ(ROK)が血管平滑筋異常収縮の重要なシグナル分子として知られるが、ROKの上流のシグナル伝達機構は不明であったため、特効薬が開発されず、血管攣縮は治療抵抗性である。本研究成果は異常収縮刺激時にカルパイン・プロテアーゼにより生成されたビメンチン断片が血管平滑筋異常収縮のシグナル伝達を亢進させる事を示唆しており、新規の血管平滑筋収縮機構の解明や血管攣縮治療薬の開発に繋がるものである。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (24 results)

All 2023 2022 2021 2020

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (19 results) (of which Invited: 1 results)

  • [Journal Article] High-efficient CRISPR/Cas9-mediated gene targeting to establish cell models of ciliopathies2023

    • Author(s)
      Hosoba Kosuke、Morita Tomoka、Zhang Ying、Kishi Hiroko、Yamamoto Takashi、Miyamoto Tatsuo
    • Journal Title

      Methods in Cell Biology

      Volume: 175 Pages: 85-95

    • DOI

      10.1016/bs.mcb.2022.07.020

    • ISBN
      9780443185861
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibitory mechanism of tangeretin, a citrus flavone on the sphingosylphosphorylcholine (SPC)-induced vascular smooth muscle contraction.2022

    • Author(s)
      Nan Li, Ying Zhang, Tomoka Morita, Hiroko Kishi, Sei Kobayashi.
    • Journal Title

      J Pharmacol Sci.

      Volume: 149 Issue: 4 Pages: 189-197

    • DOI

      10.1016/j.jphs.2022.05.002

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hesperetin Inhibits Sphingosylphosphorylcholine-Induced Vascular Smooth Muscle Contraction by Regulating the Fyn/Rho-Kinase Pathway2022

    • Author(s)
      Lu Qian、Kishi Hiroko、Zhang Ying、Morita Tomoka、Kobayashi Sei
    • Journal Title

      Journal of Cardiovascular Pharmacology

      Volume: 79 Issue: 4 Pages: 456-466

    • DOI

      10.1097/fjc.0000000000001210

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Paxillin controls actin stress fiber formation and migration of vascular smooth muscle cells by directly binding to the active Fyn2021

    • Author(s)
      Zhang Ying、Kishi Hiroko、Morita Tomoka、Kobayashi Sei
    • Journal Title

      The FASEB Journal

      Volume: 35 Issue: 12

    • DOI

      10.1096/fj.202101035rr

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn2020

    • Author(s)
      Kurahara Lin Hai、Hiraishi Keizo、Yamamura Aya、Zhang Ying、Abe Kohtaro、Yahiro Eiji、Aoki Mikiko、Koga Kaori、Yokomise Hiroyasu、Go Tetsuhiko、Ishikawa Kaori、Bo Zhang、Kishi Hiroko、Kobayashi Sei、Aoki-Shoi Narumi、Toru Satoh、Inoue Ryuji、Hirano Katsuya
    • Journal Title

      Journal of Molecular and Cellular Cardiology

      Volume: 148 Pages: 50

    • DOI

      10.1016/j.yjmcc.2020.08.013

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] The role of vimentin cleavage in the signal transduction of abnormal vascular smooth muscle contraction2023

    • Author(s)
      Hiroko Kishi, Keisuke Shigenobu, Tatsuo Miyamoto
    • Organizer
      日本生理学会第100回記念大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 血管平滑筋異常収縮の分子機構におけるカルパイン活性化およびビメンチン断片化の役割2022

    • Author(s)
      岸 博子
    • Organizer
      筋生理の集い
    • Related Report
      2022 Annual Research Report
  • [Presentation] 血管平滑筋異常収縮のシグナル伝達におけるカルパイン活性化およびビメンチン断片化の役割の解明2022

    • Author(s)
      岸 博子、森田 知佳、張 影、李 楠、宮本 達雄
    • Organizer
      第74回日本生理学会中国四国地方会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 血管平滑筋異常収縮のシグナル伝達におけるカルパイン活性化および中間径フィラメントビメンチン断片化の役割の解明2022

    • Author(s)
      岸 博子、路 倩、森田 知佳、張 影、李 楠、小林 誠
    • Organizer
      第64回日本平滑筋学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Paxillin は活性型Fyn に直接結合することにより血管平滑筋細胞のストレスファイバー形成と細胞遊走を制御する2022

    • Author(s)
      張 影、森田 知佳、小林 誠、岸 博子、宮本 達雄
    • Organizer
      第64回日本平滑筋学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] The role of vimentin cleavage and calpain in the Ca2+-sensitization of vascular smooth muscle contraction2022

    • Author(s)
      Hiroko Kishi, Qian Lu, Tomoka Morita, Ying Zhang, Nan Li, Sei Kobayashi
    • Organizer
      第99回日本生理学会大会合同大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 血管平滑筋異常収縮のシグナル伝達におけるカルパインの役割の解明2021

    • Author(s)
      岸 博子、路 倩、森田 知佳、張 影、呂 博超、李 楠、小林 誠
    • Organizer
      第63回日本平滑筋学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] The role of calpain activation and vimentin cleavage in Ca2+-sensitization of vascular smooth muscle contraction2021

    • Author(s)
      Hiroko Kishi, Qian Lu, Tomoka Morita, Ying Zhang, Bochao Lyu, Min Zhang, Nan Li, Minhui Xu, Sei Kobayashi
    • Organizer
      第126回 日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Deletion of Paxillin Attenuates Sphingosylphosphorylcholine (SPC)-Induced Abnormal Contraction of Vascular Smooth Muscle by Inhibiting Rho-kinase Activity2021

    • Author(s)
      Ying Zhang, Tomoka Morita, Bochao Lyu, Dan Cui, Hiroko Kishi, Min Zhang, Qian Lu, Nan Li, Eiji Ikeda, Sei Kobayashi
    • Organizer
      第126回 日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Sphingosylphosphorylcholine induced contraction in basilar arteries of Fyn knockout mice.2021

    • Author(s)
      Tomoka Morita, Ying Zhang, Hiroko Kishi, Sei Kobayashi
    • Organizer
      第126回 日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Madagascine induces vasodilatation via AMPK-mediated eNOS activation and ROCK inhibition2021

    • Author(s)
      Bochao Lyu, Dapeng Chen, Yuan Lin, Ying Zhang, Tomoka Morita, Hiroko Kishi, Sei Kobayashi
    • Organizer
      第126回 日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] The inhibitory effect and mechanism exploration of compound H on sphingosylphosphorylcholine (SPC)-induced contraction in vascular smooth muscle2021

    • Author(s)
      Qian Lu, Bochao Lyu, Ying Zhang, Tomoka Morita, Hiroko Kishi, Min Zhang, Nan Li, Minhui Xu, Sei Kobayashi
    • Organizer
      第126回 日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Molecular mechanism of component T inhibiting abnormal vascular contraction and migration of MDA-MB-231 cancer cells2021

    • Author(s)
      Nan Li, Min Zhang, Bochao Lyu, Ying Zhang, Hiroko Kishi, Tomoka Morita, Sei Kobayashi
    • Organizer
      第126回 日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Compound B from traditional Chinese medicine inhibits the Rho-kinase (ROK)-mediated Ca2+-sensitization of vascular smooth muscle contraction induced by a spasmogen, sphingosylphosphorylcholine (SPC)2021

    • Author(s)
      Minhui Xu, Min Zhang, Bochao Lyu, Qian lu, Nan li, Ying Zhang, Tomoka Morita, Hiroko Kishi, Sei Kobayashi
    • Organizer
      第126回 日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] SPC/Fyn/ROK系による血管平滑筋収縮のCa2+-sensitizationにおけるカルパインの活性化とビメンチン断片化の役割の解明2020

    • Author(s)
      岸 博子、路 倩、森田 知佳、張 影、呂 博超、張 敏、李 楠、徐 敏慧、小林 誠
    • Organizer
      第62回日本平滑筋学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] スフィンゴシルホスホリルコリン(SPC)による血管平滑筋のCa2+感受性収縮におけるパキシリンの役割2020

    • Author(s)
      張 影、呂 博超、森田 知佳、崔 丹、岸 博子、張 敏、路 倩、李 楠、池田 栄二、小林 誠
    • Organizer
      第62回日本平滑筋学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Madagascine induces vasodilatation via activation of AMPK2020

    • Author(s)
      Bochao Lyu, Dapeng Chen, Yuan Lin, Ying Zhang, Tomoka Morita, Hiroko Kishi, Sei Kobayashi
    • Organizer
      第62回日本平滑筋学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Compound H inhibits sphingosylphosphorylcholine-induced contraction via suppressing Fyn/Rho-kinase pathway in vascular smooth muscle2020

    • Author(s)
      Qian Lu, Bochao Lyu, Ying Zhang, Hiroko Kishi, Tomoka Morita, Min Zhang, Nan Li, Minhui Xu, Sei Kobayashi
    • Organizer
      第62回日本平滑筋学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] The inhibitory mechanism of T on MDA-MB-231 breast cancer cell migration and the mechanism of inhibiting the SPC-induced abnormal contraction.2020

    • Author(s)
      Nan Li, Min Zhang, Bochao Lyu, Ying Zhang, Hiroko Kishi, Tomoka Morita, Sei Kobayashi
    • Organizer
      第62回日本平滑筋学会総会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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