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Glucagon-dependent autonomic regulatory system and its role in cardiovascular disease

Research Project

Project/Area Number 19H03651
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionNagoya University

Principal Investigator

Yasuko Bando  名古屋大学, 医学部附属病院, 講師 (60452190)

Co-Investigator(Kenkyū-buntansha) 林 良敬  名古屋大学, 環境医学研究所, 教授 (80420363)
清野 祐介  藤田医科大学, 医学部, 准教授 (80534833)
室原 豊明  名古屋大学, 医学系研究科, 教授 (90299503)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Keywords心不全 / グルカゴン / 交感神経 / 神経内分泌系 / 糖尿病 / アドレナリン
Outline of Research at the Start

代表者らは、グルカゴン欠損マウス(Gcg-null)の心臓を解析し、高血圧と心肥大を伴う収縮機能不全性心不全を呈することを発見した(投稿準備中)。その機序には、Gcg欠損により、副腎アドレナリン分泌を制御する責任分子の生理的抑制制御の逸脱が起こり、Adrの過剰分泌を引き起こすことを解明し現在その責任分子X関連シグナリングの探索と、このGcgによる新たな神経―内分泌制御系の病態意義に関して研究を継続している。本研究は糖尿病専門医との連携により代表者らが発見したGcg依存性交感神経制御機構の解析結果を発展応用させ、交感神経活性評価の血液サンプルによる簡便なサロゲート診断法や治療法の開発を目指す。

Outline of Final Research Achievements

Mice with functional deficiency of the preproglucagon gene (GCG-null mice) develop hypertension and heart failure (HF), These findings were reversed by administration supplemental injection of GCG (Sup-GCG) or adrenergic β1-receptor blocker. Mechanistically GCG-null mice exhibited adrenal hypertrophy with upregulation of X, a key enzyme that synthesizes Y in a protein kinase A (PKA)-dependent fashion.
Our data identifies GCG as a key determinant of murine adrenomedullary development and function, defending catecholamine-related disorders such as cardiovascular disease.
Our study revealed the distinct action of pharmacological GCG injection from physiological GCG that regulates adrenomedullary differentiation and subsequent rise in circulating Ep concentration in health and disease. The GCG homeostasis is essential for compensatory defense against neurohormonal stress in response to HF.

Academic Significance and Societal Importance of the Research Achievements

内因性のGcgは、過剰な交感神経活性状態に対する生体防御反応であり、Gcgが生来低下あるいは長期間のストレスにより枯渇が生じた場合、心事故が起きやすくなる。我々の研究成果は、健常者の心血管事故(突然死)の予防においても有用である可能性が期待できる。更なる例としては、より安全な糖尿病治療薬の開発への期待である。昨今、新たな糖尿病治療薬としてGcg抑制型糖尿病治療薬の開発が進んでいるが、我々の知見と同様、Gcg機能抑制により高血圧など循環器系副作用が生じることが報告されており、糖尿病治療薬開発においても、本研究成果は配慮すべきエビデンスを示唆する応用性・創造性の高い研究成果であることが期待される。

Report

(3 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (25 results)

All 2022 2021 2020 2019

All Journal Article (10 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 7 results) Book (5 results)

  • [Journal Article] Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.2021

    • Author(s)
      Pu Z, Shimizu Y, Tsuzuki K, Suzuki J, Hayashida R, Kondo K, Fujikawa Y, Unno K, Ohashi K, Takefuji M, Bando YK, Ouchi N, Calvert JW, Shibata R, Murohara T.
    • Journal Title

      Arterioscler Thromb Vasc Biol.

      Volume: - Issue: 6 Pages: 2006-2018

    • DOI

      10.1161/atvbaha.121.316191

    • NAID

      120007178394

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure2021

    • Author(s)
      Tsutsui H, Ide T, Ito H, Kihara Y, Kinugawa K, Kinugawa S, Makaya M, Murohara T, Node K, Saito Y, Sakata Y, Shimizu W, Yamamoto K, Bando Y, Iwasaki YK, Kinugasa Y, Mizote I, Nakagawa H, Oishi S, Okada A, Tanaka A, Akasaka T, Ono M, Kimura T, Kosaka S, Kosuge M, Momomura SI.
    • Journal Title

      J Card Fail.

      Volume: 27 Issue: 12 Pages: 1404-1444

    • DOI

      10.1016/j.cardfail.2021.04.023

    • NAID

      130008119963

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia2021

    • Author(s)
      Ishihama Sohta、Ouchi Noriyuki、Sakaguchi Teruhiro、Tsuda Takuma、Kato Katsuhiro、Yagyu Hiroaki、Wettschureck Nina、Kubota Naoto、Offermanns Stefan、Kadowaki Takashi、Murohara Toyoaki、Takefuji Mikito
    • Journal Title

      The FASEB Journal

      Volume: 35 Issue: 12 Pages: 1-11

    • DOI

      10.1096/fj.202100882r

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia2021

    • Author(s)
      Tsuzuki Kazuhito、Shimizu Yuuki、Suzuki Junya、Pu Zhongyue、Yamaguchi Shukuro、Fujikawa Yusuke、Kato Katsuhiro、Ohashi Koji、Takefuji Mikito、Bando Yasuko K.、Ouchi Noriyuki、Calvert John W.、Shibata Rei、Murohara Toyoaki
    • Journal Title

      Journal of the American Heart Association

      Volume: 10 Issue: 16

    • DOI

      10.1161/jaha.121.020896

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice2021

    • Author(s)
      Fang Lixin、Ohashi Koji、Otaka Naoya、Ogawa Hayato、Hiramatsu-Ito Mizuho、Kawanishi Hiroshi、Bando Yasuko K、Shibata Rei、Shimizu Yuuki、Kato Katsuhiro、Takikawa Tomonobu、Ozaki Yuta、Takefuji Mikito、Murohara Toyoaki、Ouchi Noriyuki
    • Journal Title

      Cardiovascular Research

      Volume: ー Issue: 6 Pages: 1597-1610

    • DOI

      10.1093/cvr/cvab179

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 糖尿病における心不全発症の病態と分子機序 - 糖尿病性心筋症とは? -2020

    • Author(s)
      坂東泰子
    • Journal Title

      心臓

      Volume: 52 Pages: 14-18

    • NAID

      130007995633

    • Related Report
      2019 Annual Research Report
  • [Journal Article] インクレチン関連薬と心リモデリング - HFpEFでの役割.2020

    • Author(s)
      坂東泰子
    • Journal Title

      心臓

      Volume: 52 Pages: 237-246

    • NAID

      130008028584

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin.2019

    • Author(s)
      Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, Amano M, Kato K, Tsuda T, Eguchi S, Ishihama S, Mori Y, Yura Y, Yoshida T, Unno K, Okumura T, Ishii H, Shimizu Y, Bando YK, Ohashi K, Ouchi N, Enomoto A, Offermanns S, Kaibuchi K, Murohara T.
    • Journal Title

      Circulation.

      Volume: 140 Issue: 21 Pages: 1737-1752

    • DOI

      10.1161/circulationaha.119.041019

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction.2019

    • Author(s)
      Hara A, Kobayashi H, Asai N, Saito S, Higuchi T, Kato K, Okumura T, Bando YK, Takefuji M, Mizutani Y, Miyai Y, Saito S, Maruyama S, Maeda K, Ouchi N, Nagasaka A, Miyata T, Mii S, Kioka N, Worthley DL, Murohara T, Takahashi M, Enomoto A.
    • Journal Title

      Circ. Res.

      Volume: 125 Issue: 4 Pages: 414-430

    • DOI

      10.1161/circresaha.119.314806

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cardiomyocytes capture stem cell-derived, anti-apoptotic microRNA-214 via clathrin-mediated endocytosis in acute myocardial infarction.2019

    • Author(s)
      Eguchi S, Takefuji M, Sakaguchi T, Ishihama S, Mori Y, Tsuda T, Takikawa T, Yoshida T, Ohashi K, Shimizu Y, Hayashida R, Kondo K, Bando YK, Ouchi N, Murohara T.
    • Journal Title

      J Biol Chem.

      Volume: 294 Issue: 31 Pages: 11665-11674

    • DOI

      10.1074/jbc.ra119.007537

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Neuroendocrine disorder in cardiometabolic disease -The last black box for heart failure pathophysiology-2022

    • Author(s)
      坂東泰子
    • Organizer
      第86回日本循環器学会学術集会 プレナリーセッション
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 新規心不全治療薬の使い方(SGLT2阻害薬)2022

    • Author(s)
      坂東泰子
    • Organizer
      日本循環器連合up-to-dateセミナー(日本心不全学会)
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Glucose-dependent insulinotropic peptide (GIP) may play a regulatory role in the cardiac aging via modulating cardiac lipid metabolism2021

    • Author(s)
      Yasheng, R; Bando, YK; Kamihara, T; Nishimura, K; Murohara, T
    • Organizer
      3th Asia-Pacific Cardio Metabolic Syndrome (APCMS2020) Congress
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 糖尿病合併症としての心不全:ステージA/B心不全予防への課題2021

    • Author(s)
      Bando, YK
    • Organizer
      第36回日本糖尿病合併症学会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ATVB in Oncocardiology2021

    • Author(s)
      Bando YK
    • Organizer
      The 4st JCS Council Forum on Basic CardioVascular Research
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Impaired Autophagic Off-rate Is Responsible For Cardiac Aging Via Oxidative Stress2019

    • Author(s)
      Bando, YK; Kamihara, TK; Nishimura, KN; Yasheng, RY; Murohara, TM
    • Organizer
      Scientific Session 2019 of the American-Heart-Association
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Glucose-dependent insulinotropic peptide is essential for maintenance of cardiac lipid metabolism via FGF21-dependent pathway.2019

    • Author(s)
      Yasheng, RY; Bando, YK; Kamihara, TK; Nishimura, KN; Murohara, TM
    • Organizer
      European-Society-of-Cardiology Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of glucagon family in cardiac pathophysiology -Friend o foe? (合同シンポジウム1)「メタボリック研究の最前線」2019

    • Author(s)
      坂東泰子
    • Organizer
      CVMW2019心血管代謝週間
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Know Diabetes by Heart -糖尿病から心腎連関を識る2019

    • Author(s)
      坂東泰子
    • Organizer
      第23回日本心不全学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Innovation in Cardio-Diabetology―循環器診療における重要な変革期を迎えて2019

    • Author(s)
      坂東泰子
    • Organizer
      第83回日本循環器学会学術集会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Book] 循環器疾患 最新の治療 2022-20232022

    • Author(s)
      坂東泰子、室原 豊明
    • Total Pages
      520
    • Publisher
      南江堂
    • ISBN
      9784524229956
    • Related Report
      2021 Annual Research Report
  • [Book] ザ・ベーシックメソッド 心不全 薬物治療2021

    • Author(s)
      坂東泰子、室原 豊明
    • Total Pages
      299
    • Publisher
      メジカルビュー社
    • ISBN
      9784758319683
    • Related Report
      2021 Annual Research Report
  • [Book] 「臨床循環器病学」第11章 生活習慣と心疾患 A 2型糖尿病2021

    • Author(s)
      坂東泰子、室原 豊明
    • Total Pages
      847
    • Publisher
      文光堂
    • ISBN
      9784830619670
    • Related Report
      2021 Annual Research Report
  • [Book] The ESC Handbook of Cardiovascular Pharmacotherapy2021

    • Author(s)
      坂東泰子、室原 豊明
    • Total Pages
      929
    • Publisher
      Oxford University Press
    • ISBN
      9780198759935
    • Related Report
      2021 Annual Research Report
  • [Book] Q&Aでわかる!糖尿病×循環器疾患の治療 血糖管理だけではない新しい考え方」糖尿病性心筋症の定義とその原因は?2021

    • Author(s)
      坂東泰子、室原 豊明
    • Total Pages
      209
    • Publisher
      南江堂
    • ISBN
      9784758319669
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2024-01-30  

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