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Anti-inflammatory approach targeting calcium/calmodulin-dependent protein kinase as a novel therapeutic strategy to the heart failure

Research Project

Project/Area Number 19K23969
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0902:General internal medicine and related fields
Research InstitutionYamaguchi University

Principal Investigator

Suetomi Takeshi  山口大学, 医学部附属病院, 診療助教(4日/週) (40749842)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsカルモジュリン依存性キナーゼ / マクロファージ / 心筋細胞 / 慢性炎症 / 心不全 / 圧負荷 / 心筋リモデリング / 炎症 / インフラマソーム / カルモジュリンキナーゼ
Outline of Research at the Start

最近の大規模臨床試験の結果から、心機能低下に対する炎症の関与が再び注目されている。また心筋細胞内のカルシウム・カルモジュリンキナーゼⅡ(CaMKⅡ)活性化に伴う、マクロファージの心筋への誘導や炎症シグナル拡散がその一因であることが明らかになった。本研究では「心筋細胞での炎症シグナル発生」および「心筋細胞から他の細胞へのシグナル拡散」を標的とした、新しい心不全治療法の確立を目指す。

Outline of Final Research Achievements

The potential efficacy of anti-inflammatory therapy was shown by the results of the recently published clinical trials in which a significant decrease in adverse cardiac events was observed in patients treated by inhibitions of sterile inflammation. We investigated how the inflammatory signals from cardiomyocytes propagate to other cells. Elevated inflammatory gene expressions and inflammasome activations are observed in macrophages when cocultured with osmotic-stretched neonatal mouse cardiomyocytes. These responses are regulated by the Calcium/calmodulin-dependent protein kinase(CaMKII) in macrophage.

Academic Significance and Societal Importance of the Research Achievements

一連の結果から、心筋負荷から生じる炎症シグナルがCaMKII依存性にマクロファージに影響しリモデリングに寄与することが示唆された。ただし今回の研究期間では細胞外小胞取り込みの直接的な確認には至っておらず、マクロファージの反応の違いが、細胞外小胞の取り込みの違いによって生じているかは現時点では明らかではない。また、マクロファージ以外の非心筋細胞の反応についても十分な評価ができておらず、今後の課題である。CaMKIIを標的とすることで、より選択的で、免疫抑制の副作用を回避した炎症治療法につながる可能性があり、引き続き上記の機序を明らかにしたい。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (4 results)

All 2020 2019

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Inflammation in nonischemic heart disease: initiation by cardiomyocyte CaMKII and NLRP3 inflammasome signaling2019

    • Author(s)
      Suetomi Takeshi、Miyamoto Shigeki、Joan Heller Brown
    • Journal Title

      American Journal of Physiology-Heart and Circulatory Physiology

      Volume: 317 Issue: 5 Pages: H877-H890

    • DOI

      10.1152/ajpheart.00223.2019

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Sterile Inflammation through CaMKII Signaling in non-ischemic heart failure2020

    • Author(s)
      Takeshi Suetomi
    • Organizer
      The 4th JCS Council Forum on Basic CardioVascular Research
    • Related Report
      2020 Annual Research Report
  • [Presentation] Anti-inflammatory approach for heart failure targeting Calcium-Calmodulin dependent protein kinase2020

    • Author(s)
      Takeshi Suetomi
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Calcium/calmodulin-dependent Protein Kinase II (CaMKII) Signaling in Cardiomyocytes Initiates Inflammasome Required for Adverse Cardiac Remodeling in Response to Pressure Overload2019

    • Author(s)
      Takeshi Suetomi, Andrew Willeford, Cameron Brand, Shigeki Miyamoto, Joan Heller Brown
    • Organizer
      American Heart Association Scientific Sessions 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-09-03   Modified: 2022-01-27  

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