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Clarification of molecular mechanisms in the pathogenesis of heart failure mediated by DNA damage response

Research Project

Project/Area Number 19K17607
Research Category

Grant-in-Aid for Early-Career Scientists

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

Principal Investigator

SATO MICHIO  熊本大学, 生命資源研究・支援センター, 特任助教 (10833410)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords心不全 / DNA損傷応答 / HMGB2 / lncRNA / AK141659 / 2500002B13Rik / HMGB2 / 圧負荷誘導性心不全 / p53 / DNA Damage Response
Outline of Research at the Start

DNA損傷応答(DNA Damage Response: DDR)は、細胞のゲノム恒常性維持および癌抑制メカニズムの一つとして重要な役割を担っている。一方で近年、不適切なDDRが心不全増悪の要因の一つとして注目されている。しかし、心不全増悪に関わるDDRのメカニズムや制御機構については十分な解明がなされていない。
申請者は圧負荷誘導心不全モデルを用いた心不全病態形成初期におけるプロテオーム解析より、DNA修復に関与するHmgb2遺伝子を同定した。
本申請研究は心不全形成におけるHMGB2とDDRの分子学的メカニズムを解明することで、新規の心不全治療ターゲットを模索するための基盤研究となる。

Outline of Final Research Achievements

In this study, we focused on the DNA damage response as a factor that promotes the pathogenesis of heart failure and analyzed it using the mouse transverse aortic constriction (TAC) model. As a result, we found that Hmgb2 was markedly increased and the adjacent long non-coding RNA (lncRNA) AK141659 was significantly decreased in the situation of heart failure. In addition, AK141659 was found to have a cardioprotective effect. Furthermore, we found that AK141659 exerts its anti-cardiac effects by reducing the "DNA damage response".

Academic Significance and Societal Importance of the Research Achievements

心不全は未だ予後不良であり、超高齢社会の到来により心不全患者数は今後も増加が予測されている。また、心不全は健康寿命延伸の大きな阻害要因でもあり、効果的な治療法の開発が望まれている。一般に、加齢や高血圧などにより、心筋細胞におけるミトコンドリアの機能が低下し、その結果、DNA損傷を引き起こす活性酸素種(ROS)の産生が増加する。近年、このROSや、DNA損傷応答の活性化が心不全の発症・増悪の原因として注目されている。本研究で同定した新規lncRNAは、DNA損傷応答を軽減することで抗心不全心作用を示す。そのため、本研究の成果は、既存の治療法とは異なる心不全治療法の開発につながることが期待される。

Report

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

    (20 results)

All 2021 2020 2019 Other

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 5 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (2 results) Remarks (2 results)

  • [Journal Article] The lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis2021

    • Author(s)
      Michio Sato, Tsuyoshi Kadomatsu, Keishi Miyata, Junco S Warren, Zhe Tian, Shunshun Zhu, Haruki Horiguchi, Jun Morinaga, Taichi Sugizaki, Kaname Hirashima, Kumiko Yoshinobu, Mai Imasaka, Masatake Araki, Yoshihiro Komohara, Tomohiko Wakayama, Shinichi Nakagawa, Sarah Franklin, Koichi Node, Kimi Araki, Yuichi Oike
    • Journal Title

      Nature communications

      Volume: in press

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Circulating angiopoietin-like protein 2 levels and arterial stiffness in patients receiving maintenance hemodialysis: A cross-sectional study.2020

    • Author(s)
      Fukami H, Morinaga J, Okadome Y, Nishiguchi Y, Iwata Y, Kanki T, Nakagawa T, Izumi Y, Kakizoe Y, Kuwabara T, Horiguchi H, Sato M, Kadomatsu T, Miyata K, Tajiri T, Oike Y, Mukoyama M.
    • Journal Title

      Atherosclerosis.

      Volume: 315 Pages: 18-23

    • DOI

      10.1016/j.atherosclerosis.2020.10.890

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis2020

    • Author(s)
      Horiguchi Haruki、Kadomatsu Tsuyoshi、Miyata Keishi、Terada Kazutoyo、Sato Michio、Torigoe Daisuke、Morinaga Jun、Moroishi Toshiro、Oike Yuichi
    • Journal Title

      Oncogene

      Volume: 40 Issue: 1 Pages: 55-67

    • DOI

      10.1038/s41388-020-01505-7

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice2019

    • Author(s)
      Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
    • Journal Title

      Circulation Journal

      Volume: 83 Issue: 2 Pages: 368-378

    • DOI

      10.1253/circj.CJ-18-0925

    • NAID

      130007557092

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2019-01-25
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study2019

    • Author(s)
      Morinaga J, Kakuma T, Fukami H, Hayata M, Uchimura K, Mizumoto T, Kakizoe Y, Miyoshi T, Shiraishi N, Adachi M, Izumi Y, Kuwabara T, Okadome Y, Sato M, Horiguchi H, Sugizaki T, Kadomatsu T, Miyata K, Tajiri S, Tajiri T, Tomita K, Kitamura K, Oike Y, Mukoyama M.
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 印刷中 Issue: 5 Pages: 854-860

    • DOI

      10.1093/ndt/gfz236

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aging- and obesity-related peri-muscular adipose tissue accelerates muscle atrophy2019

    • Author(s)
      Zhu Shunshun、Tian Zhe、Torigoe Daisuke、Zhao Jiabin、Xie Peiyu、Sugizaki Taichi、Sato Michio、Horiguchi Haruki、Terada Kazutoyo、Kadomatsu Tsuyoshi、Miyata Keishi、Oike Yuichi
    • Journal Title

      PLOS ONE

      Volume: 14 Issue: 8 Pages: e0221366-e0221366

    • DOI

      10.1371/journal.pone.0221366

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] The IncRNA Caren Protects Against Heart Failure by Inactivating the ATM-DNA Damage Response Pathway and Activating Mitochondrial Biogenesis2021

    • Author(s)
      Michio Sato
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 血液透析患者における血中ANGPTL2値と死亡リスクの関連2020

    • Author(s)
      佐藤迪夫、森永 潤、向山政志、尾池雄一
    • Organizer
      第20回 日本抗加齢医学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Identification of a Novel Cardiomyocyte-enriched Long Noncoding RNA Counteracting Against Heart Failure Development.2020

    • Author(s)
      Michio Sato, Keishi Miyata, Tsuyoshi Kadomatsu, Yuichi Oike
    • Organizer
      Basic Cardiovascular Science (BCVS) 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] lncRNA Caren制御による寿命延伸への試み2020

    • Author(s)
      佐藤迪夫、宮田敬士、門松 毅、尾池雄一
    • Organizer
      AMED「老化メカニズムの解明・制御プロジェクト」片桐拠点2020若手研究者発表会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Identification of a novel cardiomyocyte-enriched long noncoding RNA counteracting against heart failure development2020

    • Author(s)
      Michio Sato, Keishi Miyata, Tsuyoshi Kadomatsu, Yuichi Oike
    • Organizer
      第4回 Basic Cardiovascular Research (BCVR)
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] The novel long noncoding RNA Caren protects against heart failure by inactivating Hint1-ATM signaling induced DNA damage response.2020

    • Author(s)
      Michio Sato, Keishi Miyata, Tsuyoshi Kadomatsu, Yuichi Oike
    • Organizer
      AMED-CREST 「恒常性領域」&「適応・修復領域」合同国際シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice2020

    • Author(s)
      Michio Sato
    • Organizer
      第84回 日本循環器学会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 内因性HMGB2の欠損はマウス圧負荷誘導性心不全モデルにおける心不全を増悪させる2019

    • Author(s)
      佐藤 迪夫、宮田 敬士、尾池 雄一
    • Organizer
      Research planet 2019
    • Related Report
      2019 Research-status Report
  • [Presentation] The long noncoding RNA Caren protects against heart failure in mice2019

    • Author(s)
      Michio Sato, Keishi Miyata, Tsuyoshi Kadomatsu, Koichi Node, Yuichi Oike
    • Organizer
      第3回日本循環器学会基礎研究フォーラム(BCVR)
    • Related Report
      2019 Research-status Report
  • [Presentation] 内因性HMGB2の欠損はマウス圧負荷誘導性 心不全モデルにおける心不全を増悪させる2019

    • Author(s)
      佐藤 迪夫
    • Organizer
      脳心血管抗加齢研究会・日本抗加齢協会第4回学術フォーラム
    • Related Report
      2019 Research-status Report
  • [Book] 循環器内科2020

    • Author(s)
      佐藤迪夫、野出孝一
    • Total Pages
      6
    • Publisher
      科学評論社
    • Related Report
      2020 Annual Research Report
  • [Book] 循環器内科 第87巻第4号2020

    • Author(s)
      佐藤 迪夫
    • Total Pages
      6
    • Publisher
      科学評論社
    • Related Report
      2019 Research-status Report
  • [Remarks] 熊本大学大学院生命科学研究部 分子遺伝学講座

    • URL

      http://www.kumamoto-u-molgene.jp/

    • Related Report
      2020 Annual Research Report
  • [Remarks] 熊本大学大学院 生命科学研究部 分子遺伝学講座

    • URL

      http://www.kumamoto-u-molgene.jp/

    • Related Report
      2019 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2022-01-27  

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