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The role of a lipid mediator on cardiac cell death in the pathogenesis of heart failure

Research Project

Project/Area Number 20K08491
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionOsaka University

Principal Investigator

TANEIKE Manabu  大阪大学, 大学院医学系研究科, 講師 (30609756)

Co-Investigator(Kenkyū-buntansha) 上田 宏達  大阪大学, 大学院医学系研究科, 招へい教員 (30865746)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords心不全 / 細胞死 / 脂質メディエーター / 心筋炎症
Outline of Research at the Start

心不全の発症進展過程における炎症とそれに引き続く心筋細胞死の根本的誘導機序の解明を狙いとする。脂質メディエーターを生成することやCaspase非依存性非アポトーシス型細胞死に関連していることが報告されているiPLA2βを解析の対象とし、その心臓および心不全における役割を解明する。そのために、細胞、野生型および遺伝子改変マウス、さらにはヒト心不全サンプルを用いて統合的な解析を行う。

Outline of Final Research Achievements

In cardiomyocyte-specific iPLA2β knockout mice, the phenotype observed in the pressure overload-induced heart failure model was improved, and necrotic cardiomyocyte death was inhibited. Lipidomics analysis and in vitro experiments using isolated neonatal rat cardiomyocytes revealed that 18:0 lysophosphatidylserine and its receptor, GPR34, were involved in the induction of the cardiomyocyte death. In global GPR34 knockout mice, the phenotype of the heart failure model was suppressed. These findings indicate that 18:0 lysophosphatidylserine produced by iPLA2β plays a detrimental role in the pathogenesis of the development and progression of pressure overload-induced heart failure by inducing cardiomyocyte necrosis through GPR34.

Academic Significance and Societal Importance of the Research Achievements

心不全は我が国を含めた先進国において主要な死因の一つであり、新規治療法の開発が臨まれている。本研究では、複数のマウス心不全モデルおよび細胞を用いた実験により、iPLA2β-LPS-GPR34-心筋細胞ネクローシスという心不全発症進展メカニズムを初めて報告した。この結果から、iPLA2βのみならず、GPR34は心不全患者に対する治療の新規分子標的となりうることが示唆されており、これまでにない新規心不全治療薬の開発への応用が期待される。また、心不全だけではなく、他の動脈硬化性疾患や炎症性疾患など、心臓以外の広い領域についても治療などに臨床応用できる可能性がある。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (8 results)

All 2023 2022 Other

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

  • [Int'l Joint Research] King's College London(英国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] King's College London(英国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] King's College London(英国)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] King's College London(英国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Lysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 342023

    • Author(s)
      Sugihara Ryuta、Taneike Manabu、Murakawa Tomokazu、Tamai Takahito、Ueda Hiromichi、Kitazume-Taneike Rika、Oka Takafumi、Akazawa Yasuhiro、Nishida Hiroki、Mine Kentaro、Hioki Ayana、Omi Jumpei、Omiya Shigemiki、Aoki Junken、Ikeda Kazutaka、Nishida Kazuhiko、Arita Makoto、Yamaguchi Osamu、Sakata Yasushi、Otsu Kinya
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 4494-4494

    • DOI

      10.1038/s41467-023-40201-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload2022

    • Author(s)
      Akazawa Yasuhiro、Taneike Manabu、Ueda Hiromichi、Kitazume-Taneike Rika、Murakawa Tomokazu、Sugihara Ryuta、Yorifuji Hiroki、Nishida Hiroki、Mine Kentaro、Hioki Ayana、Omiya Shigemiki、Nakayama Hiroyuki、Yamaguchi Osamu、Yoshimori Tamotsu、Sakata Yasushi、Otsu Kinya
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 41-41

    • DOI

      10.1038/s41598-021-03920-6

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Pressure overload induces phospholipase A2-mediated lysophosphatidylserine production, leading to necrotic cardiomyocyte death and heart failure via G protein-coupled receptor 342023

    • Author(s)
      Ryuta Sugihara, Manabu Taneike, Tomokazu Murakawa, Kinya Otsu, Yasushi Sakata
    • Organizer
      The 7th JCS Council Forum on Basic Cardiovascular Research
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Non-apoptotic Cell Death Induced by a Lipid Mediator in the Development of Heart Failure2023

    • Author(s)
      種池 学
    • Organizer
      第87回日本循環器学会学術集会
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research

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Published: 2020-04-28   Modified: 2025-01-30  

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