Glucagon-dependent autonomic regulatory system and its role in cardiovascular disease
| Project/Area Number |
19H03651
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Nagoya University |
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Principal Investigator |
Yasuko Bando 名古屋大学, 医学部附属病院, 講師 (60452190)
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| 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)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| 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)
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| 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 |
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| 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。
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| 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.
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| 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。
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Report
(3 results)
Research Products
(25 results)
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[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.
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Journal Title
Arterioscler Thromb Vasc Biol.
Volume: -
Issue: 6
Pages: 2006-2018
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
J Card Fail.
Volume: 27
Issue: 12
Pages: 1404-1444
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Circulation.
Volume: 140
Issue: 21
Pages: 1737-1752
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Circ. Res.
Volume: 125
Issue: 4
Pages: 414-430
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
J Biol Chem.
Volume: 294
Issue: 31
Pages: 11665-11674
DOI
Related Report
Peer Reviewed / Open Access
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