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Mechanisms of epicardial adipose tissue to cause atrial myocardial fibrosis and screening of compounds to suppress them

Research Project

Project/Area Number 19H04490
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 90130:Medical systems-related
Research InstitutionOita University

Principal Investigator

Takahashi Naohiko  大分大学, 医学部, 教授 (30263239)

Co-Investigator(Kenkyū-buntansha) 安部 一太郎  大分大学, 医学部, 客員研究員 (00747595)
手嶋 泰之  大分大学, 医学部, 講師 (10457608)
宮本 伸二  大分大学, 医学部, 教授 (70253797)
福井 暁  大分大学, 医学部, 助教 (70631381)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords心外膜脂肪 / 心房線維化 / 心房細動 / 線維化 / 炎症
Outline of Research at the Start

心外膜脂肪の蓄積は心血管病発症を促進する。申請者らは心房細動患者の左心房標本を解析し,“心外膜脂肪と心房筋が接する箇所に線維化が生じ,心外膜脂肪中の悪玉サイトカインの量が線維化と相関すること”を解明した。しかし左心房標本は手術時の1点でしか得られないため“心外膜脂肪がどのような機序で心房線維化を惹起するかが不明”という課題が残った。本研究の目的は,“器官培養系を用いてヒト心外膜脂脂肪が心房線維化を惹起する機序を明らかにする”ことである。さらに病理解剖の御遺体を用い脂肪の部位による線維化様式の違いを解明する。そして“器官培養系を応用し心房線維化を抑制する化合物のスクリーニング系を構築する”。

Outline of Final Research Achievements

Objective: This study aimed to examine whether Angptl2 contained in peri-left atrial EAT can induce atrial myocardial fibrosis. Methods: Human peri-left atrial EAT and abdominal subcutaneous adipose tissue (SAT) were collected from 9 autopsy cases. EAT- or SAT-conditioned medium was dropped onto the rat left atrial epicardial surface using an organo-culture system. Results: EAT-conditioned medium induced atrial fibrosis with a progressive increase in the number of myofibroblasts. The profibrotic effect of EAT was greater than that of SAT. EAT in patients with atrial fibrillation induced a more significant atrial fibrosis. Treatment with human recombinant Angptl2 induced fibrosis, which was suppressed by the concomitant treatment with Angptl2 antibody. Conclusion: The results suggested that antagonizing the expression of Angptl2 in EAT can be a novel therapeutic approach to prevent atrial fibrillation.

Academic Significance and Societal Importance of the Research Achievements

心房細動は心房線維化によってもたらされる。本研究では,器官培養法という独創的な方法によって,ヒト心外膜脂肪が心房に線維化を惹起する様子を再現できた。また,Angptl2がこの経路に関与し,これを標的とした薬物を開発すれば,あらたな心房細動治療薬になり得ることを示すことができた。心房細動患者は本邦に数百万人いるとみられ少なからずの患者に脳梗塞を引き起こす。本研究の成果を心房細動阻止に結び付けたい。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (12 results)

All 2021 2020 2019

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (8 results) (of which Int'l Joint Research: 5 results)

  • [Journal Article] Detection of fibrotic remodeling of epicardial adipose tissue in patients with atrial fibrillation: Imaging approach based on histological observation2021

    • Author(s)
      Ishii Yumi、Abe Ichitaro、Kira Shintaro、Harada Taisuke、Takano Masayuki、Oniki Takahiro、Kondo Hidekazu、Teshima Yasushi、Yufu Kunio、Shuto Takashi、Wada Tomoyuki、Nakagawa Mikiko、Shimada Tatsuo、Asayama Yoshiki、Miyamoto Shinji、Takahashi Naohiko
    • Journal Title

      Heart Rhythm O2

      Volume: 2 Issue: 4 Pages: 311-323

    • DOI

      10.1016/j.hroo.2021.05.006

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of angiopoietin-like protein 2 in atrial fibrosis induced by human epicardial adipose tissue: Analysis using an organo-culture system2020

    • Author(s)
      Kira S, Abe I, Ishii Y, Miyoshi M, Oniki T, Arakane M, Daa T, Teshima Y, Yufu K, Shimada T, Takahashi N.
    • Journal Title

      Heart Rhythm

      Volume: 17 Issue: 9 Pages: 1591-1601

    • DOI

      10.1016/j.hrthm.2020.04.027

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A traditional herbal medicine rikkunshito prevents angiotensin II-Induced atrial fibrosis and fibrillation2020

    • Author(s)
      Zhan Yinge、Abe Ichitaro、Nakagawa Mikiko、Ishii Yumi、Kira Shintaro、Miyoshi Miho、Oniki Takahiro、Kondo Hidekazu、Teshima Yasushi、Yufu Kunio、Arakane Motoki、Daa Tsutomu、Takahashi Naohiko
    • Journal Title

      Journal of Cardiology

      Volume: 76 Issue: 6 Pages: 626-635

    • DOI

      10.1016/j.jjcc.2020.07.001

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Disruption of actin dynamics regulated by Rho effector mDia1 attenuates pressure overload-induced cardiac hypertrophic responses and exacerbates dysfunction2020

    • Author(s)
      Abe Ichitaro、Terabayashi Takeshi、Hanada Katsuhiro、Kondo Hidekazu、Teshima Yasushi、Ishii Yumi、Miyoshi Miho、Kira Shintaro、Saito Shotaro、Tsuchimochi Hirotsugu、Shirai Mikiyasu、Yufu Kunio、Arakane Motoki、Daa Tsutomu、Thumkeo Dean、Narumiya Shuh、Takahashi Naohiko、Ishizaki Toshimasa
    • Journal Title

      Cardiovascular Research

      Volume: 117 Issue: 4 Pages: 1103-1117

    • DOI

      10.1093/cvr/cvaa206

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Detecting Fibrotic Remodeling of Epicardial Adipose Tissue in Patients with Atrial Fibrillation2021

    • Author(s)
      Ishii Y, Abe I, harada T, Takano M, Kira S, Kondo H, Teshima Y, yufu K, Nakagawa M, Shimada T, Miyamoto S, Takahashi N.
    • Organizer
      第85回日本循環器学会学術集会 3.26-28,2021. 横浜web
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Possible Role of Endocardium of Left Atrial Appendage in Preventing the Thrombus2021

    • Author(s)
      Ishii Y, Abe I, harada T, Takano M, Kondo H, Shinohara T, Teshima Y, yufu K, Nakagawa M, Shimada T, Miyamoto S, Takahashi N
    • Organizer
      第85回日本循環器学会学術集会 3.26-28,2021. 横浜web
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Loss of Rho effector mDia1 attenuates pressure overload-induced hypertrophic responses and exacerbates dysfunction.2020

    • Author(s)
      Abe I, Ishii Y, Miyoshi M, Kira S, Kondo H, Saito S, Teshima Y, Yufu K, Terabayashi T, Ishizaki T, Takahashi N.
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of the intramural adipose tissue of the interatrial septum on incidence of atrial fibrillation.2020

    • Author(s)
      Abe I, Miyoshi M, Ishii Y, Kira S, Oniki T, Fukuda T, Fukui A, Shinohara T, Teshima Y, Nakagawa M, Takahashi N.
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of angiopoietin-like protein 2 in atrial fibrosis induced by human epicardial adipose tissue.2020

    • Author(s)
      吉良晋太朗 安部 一太郎, 石井 悠海, 三好 美帆, 鬼木 崇裕, 福井 暁, 篠原 徹二, 手嶋 泰之, 油布 邦夫, 島田 達夫, 中川 幹子, 高橋 尚彦
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Human epicardial adipose tissue induces rat atrial myocardial fibrosis through paracrine effects: Results of organo-culture experiments2019

    • Author(s)
      Shintaro Kira, Ichitaro Abe, Yumi Ishii, Miho Miyoshi, Takahiro Oniki, Akira Fukui, Tetsuji Shinohara, Yasushi Teshima, Kunio Yufu, Tatsuo Shimada, Mikiko Nakagawa, Naohiko Takahashi
    • Organizer
      第83回日本循環器学会学術集会 3.29-31, 2019 横浜
    • Related Report
      2019 Annual Research Report
  • [Presentation] Angiopoietin-like protein(Angptl) 2 secreted from epicardial adipose tissue induces atrial myocardial fibrosis2019

    • Author(s)
      Shintaro Kira、 Ichitaro Abe、Yumi Ishii、Miyoshi Miho、Takahiro Oniki、Akira Fukui、Tetsuji Shinohara、 Yasushi Teshima、Kunio Yufu、Tatsuo Shimada、Mikiko Nakagawa、Motoki Arakane、Tsutomu Daa、Naohiko Takahashi
    • Organizer
      第66回日本不整脈心電学会学術大会 7.24-27, 2019. 横浜
    • Related Report
      2019 Annual Research Report
  • [Presentation] Angiopoietin-like protein (Angptl) 2 secreted from epicardial adipose tissue induces atrial myocardial fibrosis2019

    • Author(s)
      Shintaro Kira,Ichitaro Abe、Yasushi Teshima、Yumi Ishii、Miho Miyoshi、Takahiro Oniki、Akira Fukui、Tetsuji Shinohara、Kunio Yufu、Naohiko Takahashi
    • Organizer
      European Society of Cardiology Congress 2019 8.31-9.4, 2019. パリ/フランス
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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