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The investigation of the role of YAP in heart failure

Research Project

Project/Area Number 18K15876
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53020:Cardiology-related
Research InstitutionInternational University of Health and Welfare (2020-2021)
Tohoku University (2018-2019)

Principal Investigator

Shohei Ikeda  国際医療福祉大学, 医学部, 講師 (40808581)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsYAP / 心不全 / 圧負荷 / TEAD / OSM / 心筋脱分化 / 糖尿病性心筋症 / TEAD1 / Hippo / 糖尿病 / Yao
Outline of Final Research Achievements

In this study, I investigated the role of the Hippo deficiency and the persistent activation of YAP. Cardiac specific Hippo deficient mice showed the persistent activation of YAP in the heart. The mice showed the decrease of apoptosis and cell cycle re-entry related with YAP activation in the pressure-overload condition and finally showed severe heart failure. I found the mechanism was the cardiac dedifferentiation depended on the activation pathway of YAP-TEAD1-OSM. Furthermore I found the suppression of the pathway attenuated the heart failure. In addition, I found the cardiac activation of YAP in the model of diabetes. In the model, pressure overload induced severe heart failure accompanied cardiac dedifferentiation depended on the activation pathway of YAP-TEAD1-OSM.Finally, I found the cardiac dedifferentiation depended on the activation pathway of YAP-TEAD1-OSM in human diabetic cardiomyopathy.

Academic Significance and Societal Importance of the Research Achievements

心臓でのYAPの活性化は生存維持や増殖活性を通じて、正に働くことが報告されるが、心臓のYAPの恒常活性化が心臓に与える影響が不明であった。今回の研究で心臓のYAPの恒常活性化が予想外に心不全増悪に働くことが分かった。機序としてYAP-TEAD1-OSM経路の活性化により心筋脱分化に起因する心不全が起こることが分かった。また同様の減少は糖尿病性心筋症でも起こることが分かった。今回の結果から心臓でのYAPの適正範囲の管理が心臓機能維持に重要であることが示唆されたこと、YAPの抑制が心機能保持・心不全治療に貢献する病態が存在することが示唆され、今後の循環器病に貢献しうる研究成果であったと考える。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (7 results)

All 2022 2021 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (2 results) (of which Int'l Joint Research: 2 results) Funded Workshop (1 results)

  • [Journal Article] The role of autophagy in death of cardiomyocytes2022

    • Author(s)
      Ikeda Shohei、Zablocki Daniela、Sadoshima Junichi
    • Journal Title

      Journal of Molecular and Cellular Cardiology

      Volume: 165 Pages: 1-8

    • DOI

      10.1016/j.yjmcc.2021.12.006

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] YAP plays a crucial role in the development of cardiomyopathy in lysosomal storage diseases2021

    • Author(s)
      Ikeda Shohei、Nah Jihoon、Shirakabe Akihiro、Zhai Peiyong、Oka Shin-ichi、Sciarretta Sebastiano、Guan Kun-Liang、Shimokawa Hiroaki、Sadoshima Junichi
    • Journal Title

      Journal of Clinical Investigation

      Volume: 131 Issue: 5 Pages: 1-15

    • DOI

      10.1172/jci143173

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hippo deficiency leads to cardiac dysfunction accompanied by cardiomyocyte dedifferentiation during pressure overload.2019

    • Author(s)
      Ikeda S, Mizushima W, Sciarretta S, Abdellatif M, Zhai P, Mukai R, Fefelova N, Oka S, Nakamura M, Del Re DP, Farrance I, Park JY, Tian B, Xie LH, Kumar M, Hsu CP, Sadayappan S, Shimokawa H, Lim DS, Sadoshima J.
    • Journal Title

      Circulation Research

      Volume: 18 Issue: 2 Pages: 292-305

    • DOI

      10.1161/circresaha.118.314048

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Yes-Associated Protein (YAP) Facilitates Pressure Overload-Induced Dysfunction in the Diabetic Heart2019

    • Author(s)
      1.Ikeda S, Mukai R, Mizushima W, Zhai P, Oka SI, Nakamura M, Del Re DP, Sciarretta S, Hsu CP, Shimokawa H, Sadoshima J
    • Journal Title

      JACC Basic Transl Sci.

      Volume: 4 Issue: 5 Pages: 611-622

    • DOI

      10.1016/j.jacbts.2019.05.006

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Oncostatin M is a potential diagnostic biomarker for silent myocardial ischemia associated with patients with diabetes mellitus2021

    • Author(s)
      Shohei Ikeda, Koichi Sato, Keita Miki, Morihiko Takeda, Nobuyuki Shiba
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Oncostatin M is a potential diagnostic biomarker for silent myocardial ischemia associated with patients with diabetes mellitus2021

    • Author(s)
      Shohei Ikeda, Koichi Sato, Keita Miki, Morihiko Takeda, Nobuyuki Shiba
    • Organizer
      第85回日本循環器学会
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Funded Workshop] Scientific Sessions - American Heart Association (AHA) 2018 in Chicago, Illinois2018

    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2023-01-30  

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