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Development of novel therapeutic strategy for the treatment of pulmonary hypertension by targeting thrombin receptor

Research Project

Project/Area Number 16K09518
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Cardiovascular medicine
Research InstitutionKagawa University

Principal Investigator

Hirano katsuya  香川大学, 医学部, 教授 (80291516)

Research Collaborator Kuwabara Yukimitsu  
Abe Kohtaro  
Hirano Mayumi  
Liu Wenhua  
Hashimoto Takeshi  
Yamashita Tetsuo  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords肺高血圧症 / トロンビン受容体 / 受容体拮抗薬 / 治療薬 / 遺伝子ノックアウト / 肺高血圧 / トロンビン / 受容体 / 病態生理
Outline of Final Research Achievements

The pathological findings of the murine models of pulmonary hypertenion was demonstated to be suppressed by treatment with an antagonist of thrombin receptor PAR1 and knockout of PAR1 gene. In both cases, the vascular proliferative lesions and right ventricular hypertrophy were ameliorated. Furthermore, the expression of thrombin receptor PAR1 in pulmonary arteries was found to be up-regulated. The receptor upregulation is suggested to contribute to development of pathophysiology. The present study propose a potential of thrombin receptor PAR1 antagonist to serve as a novel therapeutic agent for the treatment of pulmonary hypertension.

Academic Significance and Societal Importance of the Research Achievements

肺高血圧症とは、右心室から出て肺を循環し、ガス交換を担う肺循環系の血圧が上昇する疾患である。この病気の成り立ちには、血管の収縮、肥厚病変、血栓による肺動脈の閉塞が重要な役割を果たすとされている。現在用いられている治療薬は、血管収縮の軽減を目指した血管拡張薬が主体である。本研究では、上記の3つの病態全てに関与し得ると考えられる凝固因子が作用し、血管収縮や肥厚病変を引き起こすトロンビン受容体PAR1を阻害すると、肺高血圧の病態が改善することを動物実験で明らかにした。PAR1拮抗薬は新たな肺高血圧治療薬と期待される。しかし、肺高血圧患者に安全に使用できるかを明らかにするにはさらなる研究が必要である。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report

Research Products

(20 results)

All 2019 2018 2017 2016

All Journal Article (7 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (12 results) (of which Int'l Joint Research: 3 results,  Invited: 5 results) Book (1 results)

  • [Journal Article] Proteinase-activated Receptor 1 Antagonism Ameliorates Experimental Pulmonary Hypertension.2019

    • Author(s)
      Kuwabara Y, Tanaka-Ishikawa M, Abe K, Hirano M, Hirooka Y, Tsutsui H, Sunagawa K, Hirano K.
    • Journal Title

      Cadiovasc Res

      Volume: in press Pages: 1357-1368

    • DOI

      10.1093/cvr/cvy284

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coagulation factor XI induces Ca2+ response and accelerates cell migration in vascular smooth muscle cells via proteinase-activated receptor 12019

    • Author(s)
      Liu W, Hashimoto T, Yamashita T, Hirano K
    • Journal Title

      Am J Physiol Cell Physiol

      Volume: 316(3)

    • DOI

      10.1152/ajpcell.00426.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protein phosphatases 1 and 2A and their naturally occurring inhibitors: current topics in smooth muscle physiology and chemical biology2017

    • Author(s)
      Takai Akira、Eto Masumi、Hirano Katsuya、Takeya Kosuke、Wakimoto Toshiyuki、Watanabe Masaru
    • Journal Title

      The Journal of Physiological Sciences

      Volume: 68 Pages: 1-17

    • DOI

      10.1007/s12576-017-0556-6

    • NAID

      40021443577

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy2017

    • Author(s)
      Guan Yu、Nakano Daisuke、Zhang Yifan、Li Lei、Liu Wenhua、Nishida Motohiro、Kuwabara Takashige、Morishita Asahiro、Hitomi Hirofumi、Mori Kiyoshi、Mukoyama Masashi、Masaki Tsutomu、Hirano Katsuya、Nishiyama Akira
    • Journal Title

      Pharmacol Sci

      Volume: 135 Pages: 81-88

    • DOI

      10.1016/j.jphs.2017.09.002

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Unique Property of the Pulmonary Artery Regarding the Smooth Muscle Effects of Proteinase-Activated Receptor 1: The Possible Contribution to the Pathogenesis of Pulmonary Hypertension2017

    • Author(s)
      Hirano Katsuya
    • Journal Title

      Diagnosis treatment of pulmonary hypertension - From bench to bedside

      Volume: N/A Pages: 77-87

    • DOI

      10.1007/978-981-287-840-3_6

    • Related Report
      2017 Research-status Report
  • [Journal Article] 肺循環薬理学研究の最前線2016

    • Author(s)
      平野勝也、山村彩
    • Journal Title

      日本薬理学雑誌

      Volume: 148 Pages: 225-225

    • Related Report
      2016 Research-status Report
  • [Journal Article] プロテイナーゼ活性化型受容体の血管生物学2016

    • Author(s)
      平野勝也
    • Journal Title

      医学のあゆみ

      Volume: 256 Pages: 489-494

    • Related Report
      2016 Research-status Report
  • [Presentation] Novel role of coagulation factor XI as a regulator of vascular smooth muscle function2019

    • Author(s)
      Hirano K, Liu W.
    • Organizer
      The 9th Federation of the Asian and Oceanian Physiological Society Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A novel function of activated coagulation factor XI as a regulator of intracellular Ca2+ signal and cell migration in vascular smooth muscle cells2018

    • Author(s)
      Liu W, Hashimoto T, Yamashita T, Hirano K
    • Organizer
      American Heart Association Scientific Session 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Novel strategy for treatment of pulmonary hypertension based on the unique property of pulmonary circulation regarding smooth muscle effect of proteinase-activated receptor 12018

    • Author(s)
      Hirano K
    • Organizer
      第95回日本生理学会大会シンポジウム「平滑筋生理学から病態生理学へのトランスレーション
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 血液凝固第XI因子は電位作動性Ca2+チャネルを介して血管平滑筋細胞にCa2+シグナルを発生させる2018

    • Author(s)
      平野勝也、劉文華、橋本剛、山下哲生
    • Organizer
      第47回日本心脈管作動物質学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Rho-Rhoキナーゼ経路がトロンビンによる内皮バリアー障害の初期事象である細胞辺縁部アクチン線維束形成に関わる2018

    • Author(s)
      平野真弓、平野勝也
    • Organizer
      第47回日本心脈管作動物質学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] トロンビン受容体を標的とする新規肺高血圧治療の提案2017

    • Author(s)
      平野勝也
    • Organizer
      第46回日本心脈管作動物質学会シンポジウム「心脈管作動物質の新展開」
    • Place of Presentation
      沖縄
    • Year and Date
      2017-02-10
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 肺循環系におけるトロンビン受容体の特性と肺高血圧における役割2017

    • Author(s)
      平野勝也
    • Organizer
      第2回日本肺高血圧・肺循環学会学術集会シンポジウム「肺高血圧症~基礎研究領域の最新知見」
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 実験的肺高血圧症に対するプロテイナーゼ活性化型受容体1(PAR1)拮抗薬の治療的効果2017

    • Author(s)
      平野勝也、桑原志実、田中真理子、阿部弘太郎、平野真弓
    • Organizer
      第59回日本平滑筋学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 血管平滑筋細胞において凝固第XI因子が引き起こすプロテイナーゼ活性化型受容体1を介した電位作動性カルシウムチャネル依存性Ca2+流入作用2017

    • Author(s)
      劉文華、橋本剛、山下哲生、平野勝也
    • Organizer
      第59回日本平滑筋学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] トロンビン受容体PAR1の阻害は肺高血圧症の病態形成を抑制する2017

    • Author(s)
      平野勝也、桑原志実、田中真理子、阿部弘太郎、平野真弓
    • Organizer
      第132回日本薬理学会近畿部会
    • Related Report
      2017 Research-status Report
  • [Presentation] 肺高血圧症の病態形成におけるトロンビン受容体PAR1の役割2016

    • Author(s)
      平野勝也
    • Organizer
      第20回日本心血管内分泌代謝学会学術集会シンポジウム「心血管内分泌学の新展開」
    • Place of Presentation
      東京
    • Year and Date
      2016-12-16
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Specific and increased expression of thrombin receptor PAR1 in pulmonary artery plays a key role in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats.2016

    • Author(s)
      Kuwabara Y, Tanaka M, Abe K, Hirano M, Hirooka Y, Sunagawa K, Hirano K
    • Organizer
      American Heart Association Scientific Session 2016
    • Place of Presentation
      New Orleans, LO, USA
    • Year and Date
      2016-11-12
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Book] Diagnosis treatment of pulmonary hypertension - From bench to bedside2017

    • Author(s)
      Katsuya Hirano
    • Total Pages
      236
    • Publisher
      Springer Singapore
    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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