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Novel role of small G protein signaling in the cardiac senescence-induced heart dysfunction

Research Project

Project/Area Number 20K08489
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionShiga University of Medical Science

Principal Investigator

Ogita Hisakazu  滋賀医科大学, 医学部, 教授 (50379236)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords心機能 / ミトコンドリア / 老化 / RhoA / 心不全 / 低分子量Gタンパク質 / 心臓 / 心筋障害
Outline of Research at the Start

超高齢社会を迎えた日本において、老化による心機能低下・心不全は急増しており、医学的のみならず社会的にも大きな問題となっている。本研究では、低分子量Gタンパク質RhoAが加齢による心機能低下にどのように関連しているか、細胞レベルから動物モデル、患者サンプルまで幅広く解析することによって、その分子メカニズムの詳細を明らかにする。この研究成果は心不全の新たな治療戦略の開発に向けた基礎医学的基盤となる。

Outline of Final Research Achievements

The main findings of this study were the cardioprotective effects of RhoA, a small GTPase, on cardiac senescence, which was certified by use of the originally generated cardiomyocyte-specific RhoA conditional knockout (cKO) mice. RhoA promoted the expression of Parkin in cardiomyocytes, and maintained the function of mitochondria in the heart. When reduced Parkin expression in the RhoA cKO heart was supplemented by the adeno-associated virus (AAV) system, cardiac senescence was almost completely recovered.

Academic Significance and Societal Importance of the Research Achievements

学術的意義として、高齢者で増加している心機能低下、心不全に関する新たな分子メカニズムを解明することができた。心不全は現在でも5年生存率約50%という予後不良の病態であり、本研究の成果は超高齢社会の日本においてこの病態を克服するための治療法開発の基盤として活用できる。例えば、心筋RhoAの発現が低下している心不全患者に対して、AAVを用いて心筋へのRhoAあるいはパーキンの補充療法を開発していくことなどが考えられる。

Report

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

    (36 results)

All 2023 2022 2021 2020 Other

All Journal Article (11 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 11 results,  Open Access: 7 results) Presentation (19 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Remarks (3 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Journal Article] RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy2023

    • Author(s)
      Soh Joanne Ern Chi、Shimizu Akio、Molla Md Rasel、Zankov Dimitar P.、Nguyen Le Kim Chi、Khan Mahbubur Rahman、Tesega Wondwossen Wale、Chen Si、Tojo Misa、Ito Yoshito、Sato Akira、Hitosugi Masahito、Miyagawa Shigeru、Ogita Hisakazu
    • Journal Title

      Journal of Biological Chemistry

      Volume: 299 Issue: 3 Pages: 102993-102993

    • DOI

      10.1016/j.jbc.2023.102993

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Vascular smooth muscle RhoA counteracts abdominal aortic aneurysm formation by modulating MAP4K4 activity2022

    • Author(s)
      Molla Md Rasel、Shimizu Akio、Komeno Masahiro、Rahman Nor Idayu A.、Soh Joanne Ern Chi、Nguyen Le Kim Chi、Khan Mahbubur Rahman、Tesega Wondwossen Wale、Chen Si、Pang Xiaoling、Tanaka-Okamoto Miki、Takashima Noriyuki、Sato Akira、Suzuki Tomoaki、Ogita Hisakazu
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 1071-1071

    • DOI

      10.1038/s42003-022-04042-z

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Associations Between Habitual Dietary Behaviors and Glutamic Acid Levels in Human Milk.2022

    • Author(s)
      Nakai S, Tateoka Y, Miyaguchi Y, Takahashi M, Ogita H.
    • Journal Title

      J Hum Lact

      Volume: - Issue: 2 Pages: 315-324

    • DOI

      10.1177/08903344221095784

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Differences Between Patients with and without Atherosclerosis in Expression Levels of Inflammatory Mediators in the Adipose Tissue Around the Coronary Artery2021

    • Author(s)
      Suzuki Tomoaki、Ogita Hisakazu、Sato Akira、Minamidate Naoshi、Hachiro Kohei
    • Journal Title

      International Heart Journal

      Volume: 62 Issue: 2 Pages: 390-395

    • DOI

      10.1536/ihj.20-585

    • NAID

      130008007468

    • ISSN
      1349-2365, 1349-3299
    • Year and Date
      2021-03-30
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell‐to‐cell contact‐mediated regulation of tumor behavior in the tumor microenvironment2021

    • Author(s)
      Sato A, Rahman NIA, Shimizu A, Ogita H
    • Journal Title

      Cancer Sci

      Volume: 112 Issue: 10 Pages: 4005-4012

    • DOI

      10.1111/cas.15114

    • NAID

      120007146544

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through αB-crystallin intracellular dynamics2021

    • Author(s)
      Nguyen LKC, Shimizu A, Soh JEC, Komeno M, Sato A, Ogita H
    • Journal Title

      J Biochem

      Volume: 170 Issue: 5 Pages: 577-585

    • DOI

      10.1093/jb/mvab066

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cardio- and reno-protective effects of dipeptidyl peptidase III in diabetic mice2021

    • Author(s)
      Komeno M, Pang X, Shimizu A, Molla MR, Yasuda-Yamahara M, Kume S, Rahman NIA, Soh JEC, Nguyen LKC, Ahmat Amin MKB, Kokami N, Sato A, Asano Y, Maegawa H, Ogita H
    • Journal Title

      J Biol Chem

      Volume: 296 Pages: 100761-100761

    • DOI

      10.1016/j.jbc.2021.100761

    • NAID

      120007045058

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stomatin-mediated inhibition of the Akt signaling axis suppresses tumor growth2021

    • Author(s)
      Rahman Nor Idayu A.、Sato Akira、Tsevelnorov Khurelbaatar、Shimizu Akio、Komeno Masahiro、Ahmat Amin Mohammad Khusni Bin、Molla Md Rasel、Soh Joanne Ern Chi、Nguyen Le Kim Chi、Wada Akinori、Kawauchi Akihiro、Ogita Hisakazu
    • Journal Title

      Cancer Research

      Volume: - Issue: 9 Pages: 2318-2331

    • DOI

      10.1158/0008-5472.can-20-2331

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pro-invasive and -metastatic activities of epithelial membrane protein 12020

    • Author(s)
      清水 昭男、扇田 久和
    • Journal Title

      生化学

      Volume: 92 Issue: 2 Pages: 216-220

    • DOI

      10.14952/SEIKAGAKU.2020.920216

    • NAID

      40022245242

    • ISSN
      0037-1017
    • Year and Date
      2020-04-25
    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome.2020

    • Author(s)
      Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
    • Journal Title

      FASEB Journal

      Volume: 34 Issue: 5 Pages: 6399-6417

    • DOI

      10.1096/fj.201902991r

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition2020

    • Author(s)
      Tomita Issei、Kume Shinji、Sugahara Sho、Osawa Norihisa、Yamahara Kosuke、Yasuda-Yamahara Mako、Takeda Naoko、Chin-Kanasaki Masami、Kaneko Tatsuroh、Mayoux Eric、Mark Michael、Yanagita Motoko、Ogita Hisakazu、Araki Shin-ichi、Maegawa Hiroshi
    • Journal Title

      Cell Metabolism

      Volume: 32 Issue: 3 Pages: 404-404

    • DOI

      10.1016/j.cmet.2020.06.020

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Novel protective role of RhoA in the senescence heart by regulating Parkin-mediated mitophagy2023

    • Author(s)
      Joanne Ern Chi Soh、清水昭男、Md Rasel Molla、扇田久和
    • Organizer
      日本循環器学会(国際留学生YIA受賞講演)
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Vascular Smooth Muscle RhoA Confers Protection Against Abdominal Aortic Aneurysm Formation by Inhibiting MAP4K4 Activity2022

    • Author(s)
      Md Rasel Molla、清水昭男、佐藤朗、鈴木友彰、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2022 Annual Research Report
  • [Presentation] RhoA regulates senescence heart by maintaining mitochondrial function via Parkin-dependent mitophagy2022

    • Author(s)
      Joanne Ern Chi Soh、清水昭男、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Transmembrane protein 168 mutation that associates with Brugada syndrome recruits αB-crystallin to reduce cardiac Nav1.5 expression on the cardiomyocyte surface2022

    • Author(s)
      Le Kim Chi Nguyen、清水昭男、佐藤朗、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Role of Afadin in vascular smooth muscle contraction via the Gq-phospholipase Cβ axis to enhance calcium signaling2022

    • Author(s)
      Md Mahbubur Rahman Khan、佐藤朗、清水昭男、米野雅大、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 非ヒト霊長類モデルを活用したドキソルビシン誘発心筋症における心筋障害因子S100A8/9の同定とその阻害による心保護2022

    • Author(s)
      佐藤朗、清水昭男、扇田久和
    • Organizer
      腫瘍循環器学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Role of transmembrane protein 168 mutation in Brugada syndrome by alteration in subcellular localization of αB-crystallin to modulate sodium channel Nav1.5 surface expression in cardiomyocytes2022

    • Author(s)
      Le Kim Chi Nguyen、清水昭男、佐藤朗、扇田久和
    • Organizer
      日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Stomatin possesses tumor-suppressive effect via the PDPK1-Akt signaling axis.2021

    • Author(s)
      Nor Idayu A. Rahman、佐藤朗、清水昭男、米野雅大、Md Rasel Molla、Joanne Ern Chi Soh、Le Kim Chi Nguyen、和田晃典、河内明宏、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2021 Research-status Report
  • [Presentation] Dipeptidyl peptidase IIIの糖尿病性腎臓病抑制機序2021

    • Author(s)
      米野雅大、Md Rasel Molla、清水昭男、扇田久和
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2021 Research-status Report
  • [Presentation] RhoA protects senescence heart by preserving mitochondrial function via Parkin2021

    • Author(s)
      Joanne Ern Chi Soh、清水昭男、Md Rasel Molla、米野雅大、扇田久和
    • Organizer
      日本循環器学会基礎研究フォーラム
    • Related Report
      2021 Research-status Report
  • [Presentation] Tumor microenvironment-mediated upregulation of stomatin for suppressing the tumor growth by inhibiting the Akt pathway2021

    • Author(s)
      扇田久和、佐藤朗
    • Organizer
      日本癌学会
    • Related Report
      2021 Research-status Report
  • [Presentation] ジペプチジルペプチダーゼIIIが糖尿病性腎臓病を抑制する作用機序2021

    • Author(s)
      米野雅大、Md Rasel Molla、清水昭男、扇田久和
    • Organizer
      日本生化学会
    • Related Report
      2021 Research-status Report
  • [Presentation] Novel protective role of RhoA in vascular smooth muscle cells against aortic aneurysm formation2021

    • Author(s)
      Md Rasel Molla、清水昭男、Nor Idayu A. Rahman、Joanne Ern Chi Soh、Le Kim Chi Nguyen、Mahbubur Rahman Khan、岡本(田中)三紀、高島範之、佐藤朗、鈴木友彰、扇田久和
    • Organizer
      日本循環器学会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Rho A rescues senescence heart by maintaining mitochondrial function via Parkin2021

    • Author(s)
      Joanne Ern Chi Soh, 清水昭男, Md Rasel Molla, 米野雅大, 扇田久和
    • Organizer
      日本循環器学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Dipeptidyl Peptidase III Prevents Cardiac Dysfunction and Nephropathy in Type II Diabetes2020

    • Author(s)
      米野雅大, 清水昭男, 扇田久和
    • Organizer
      日本循環器学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Novel mechanism for the protective effect of RhoA in vascular smooth muscle cells on abdominal aortic aneurysm2020

    • Author(s)
      Md Rasel Molla, 清水昭男, 扇田久和
    • Organizer
      日本循環器学会
    • Related Report
      2020 Research-status Report
  • [Presentation] A novel mutation in transmembrane protein 168 causes fatal ventricular arrhythmogenesis in Brugada syndrome2020

    • Author(s)
      Hisakazu Ogita, Dimitar P. Zankov, Akio Shimizu
    • Organizer
      European Society of Cardiology
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] RhoA Confers Protection Against Aortic Aneurysm by Preserving Aortic Smooth Muscle Contractility and Preventing Inflammation2020

    • Author(s)
      Md Rasel Molla, 清水昭男, 扇田久和
    • Organizer
      日本循環器学会基礎研究フォーラム
    • Related Report
      2020 Research-status Report
  • [Presentation] Novel protective effect of vascular smooth muscle RhoA on aortic aneurysm2020

    • Author(s)
      Md Rasel Molla, 清水昭男, 佐藤朗, 扇田久和
    • Organizer
      日本血管生物医学会若手研究会
    • Related Report
      2020 Research-status Report
  • [Remarks] 滋賀医科大学 分子病態生化学

    • URL

      http://www.shiga-med.ac.jp/~hqbioch2/

    • Related Report
      2022 Annual Research Report
  • [Remarks] 滋賀医科大学 生化学・分子生物学講座 分子病態生化学部門

    • URL

      http://www.shiga-med.ac.jp/~hqbioch2/

    • Related Report
      2021 Research-status Report
  • [Remarks] 滋賀医科大学 分子病態生化学ホームページ

    • URL

      http://www.shiga-med.ac.jp/~hqbioch2/

    • Related Report
      2020 Research-status Report
  • [Patent(Industrial Property Rights)] 電位治療器2023

    • Inventor(s)
      見片三郎、阿部剛代志、扇田久和
    • Industrial Property Rights Holder
      見片三郎、阿部剛代志、扇田久和
    • Industrial Property Rights Type
      特許
    • Filing Date
      2023
    • Related Report
      2022 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 心不全の治療及び/又は予防用医薬組成物2022

    • Inventor(s)
      扇田久和、佐藤朗
    • Industrial Property Rights Holder
      扇田久和、佐藤朗
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2022-196440
    • Filing Date
      2022
    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] 低密度リポタンパク質受容体ノックアウトによる脂質異常症カニクイザルの作製2021

    • Inventor(s)
      扇田久和、佐藤朗、依馬正次、築山智之
    • Industrial Property Rights Holder
      扇田久和、佐藤朗、依馬正次、築山智之
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-135524
    • Filing Date
      2021
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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