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Role of hormonal action and clonal hematopoiesis in diabetic cardiomyopathy

Research Project

Project/Area Number 21H02911
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

Murohara Toyoaki  名古屋大学, 医学系研究科, 教授 (90299503)

Co-Investigator(Kenkyū-buntansha) 坂東 泰子 (暮石泰子)  三重大学, 医学系研究科, 教授 (60452190)
柴田 玲  名古屋大学, 医学系研究科, 特任教授 (70343689)
清水 優樹  名古屋大学, 医学系研究科, 助教 (90801887)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords2型糖尿病 / 心不全 / 毛細血管障害 / グルカゴン / インクレチン / 組織虚血 / 糖尿病性心筋症 / 心筋代謝障害 / サイトカイン / 糖尿病 / 2型糖尿病 / クローン性造血 / 血管新生 / アディポカイン / 血球系幹細胞 / サイトカインストーム
Outline of Research at the Start

2型糖尿病患者は日本でも増加しており、医学的のみならず社会的に大きな問題となっている。糖尿病患者では心筋梗塞や脳卒中に代表される心血管病や心不全・がんなどの合併が非糖尿病患者よりも多く、それらの合併は患者の生命予後やQOL を左右する。糖尿病に伴う心不全のうち冠動脈疾患を伴わない、いわゆる「糖尿病性心筋症」につき、グルカゴン関連蛋白(グルカゴンやインクレチン)、クローン性造血、アディポカインの観点から機序に関する考察を加え、最終的にはそれらに関連した治療薬開発の緒を探るのが、本申請研究の主たる研究概要である。

Outline of Final Research Achievements

It has been noted that patients with type 2 diabetes mellitus frequently suffer from heart failure in addition to atherosclerotic vascular disease such as coronary artery disease. In this study, we examined how metabolic abnormalities associated with diabetes and diabetic capillary injuries are involved in the decline of cardiac function (i.e., diabetic cardiomyopathy). We focused on incretin, glucagon, and capillary and angiogenic functions. We obtained glucagon- and GLP-1-deficient mice, and our findings are now under submission for publication. We also examined whether the novel adipokines have anti-heart failure effects. In mice with myocardial ischemia, omentin showed myocardial protective effects (paper was published).

Academic Significance and Societal Importance of the Research Achievements

本研究では、糖尿病に伴い明らかな冠動脈疾患や既存の特発性心筋症が無いにも関わらず心機能が低下している病態、「糖尿病性心筋症」に関して、心筋毛細血管新生や代謝性心筋障害と、グルカゴン関連ペプチド、アディポカインなどの観点から、主に代謝性因子による関与を中心に検討した。また近年注目されている、クローン性造血と糖尿病、心不全の関連についても検討する。本研究により、糖尿病によって引き起こされる原因不明の心臓の収縮・拡張機能障害や、毛細血管障害による心機能障害のさらなる病態解明が進む。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (23 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (1 results) Journal Article (14 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 14 results,  Open Access: 13 results) Presentation (8 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results)

  • [Int'l Joint Research] Emory University(米国)

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Omentin Modulates Chronic Cardiac Remodeling After Myocardial Infarction2023

    • Author(s)
      Ito M, Shibata R, Ohashi K, Otaka N, Yamaguchi S, Ogawa H, Enomoto T, Masutomi T, Murohara T, Ouchi N.
    • Journal Title

      Circulation Reports

      Volume: 5 Issue: 2 Pages: 46-54

    • DOI

      10.1253/circrep.CR-22-0079

    • ISSN
      2434-0790
    • Year and Date
      2023-02-10
    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway2023

    • Author(s)
      Ozaki Y, Ohashi K, Otaka N, Kawanishi H, Takikawa T, Fang L, Takahara K, Tatsumi M, Ishihama S, Takefuji M, Kato K, Shimizu Y, Bando YK, Inoue A, Kuzuya M, Miura S, Murohara T, Ouchi N.
    • Journal Title

      Nature Communication

      Volume: 14 Issue: 1 Pages: 4675-4675

    • DOI

      10.1038/s41467-023-40435-2

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adipolin protects against renal injury via PPARα-dependent reduction of inflammasome activation2023

    • Author(s)
      Fang Lixin、Ohashi Koji、Hayakawa Satoko、Ogawa Hayato、Otaka Naoya、Kawanishi Hiroshi、Takikawa Tomonobu、Ozaki Yuta、Takahara Kunihiko、Tatsumi Minako、Takefuji Mikito、Shimizu Yuuki、Bando Yasuko K.、Fujishima Yuya、Maeda Norikazu、Shimomura Iichiro、Murohara Toyoaki、Ouchi Noriyuki
    • Journal Title

      iScience

      Volume: 26 Issue: 5 Pages: 106591-106591

    • DOI

      10.1016/j.isci.2023.106591

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cardiac Lymphatic Insufficiency Leads to Diastolic Dysfunction Via Myocardial Morphologic Change2023

    • Author(s)
      Pu Zhongyue、Shimizu Yuuki、Hayashi Takumi、Che Yiyang、Suzuki Junya、Tsuzuki Kazuhito、Narita Shingo、Shibata Rei、Calvert John W.、Murohara Toyoaki
    • Journal Title

      JACC: Basic to Translational Science

      Volume: 8 Issue: 8 Pages: 958-972

    • DOI

      10.1016/j.jacbts.2023.01.008

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Therapeutic Lymphangiogenesis Is a Promising Strategy for Secondary Lymphedema2023

    • Author(s)
      Shimizu Yuuki、Che Yiyang、Murohara Toyoaki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 9 Pages: 7774-7774

    • DOI

      10.3390/ijms24097774

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Corticotropin releasing hormone receptor 2 antagonist, RQ-00490721, for the prevention of pressure overload-induced cardiac dysfunction2022

    • Author(s)
      Mori Yu、Tsuchihira Ayako、Yoshida Tatsuya、Yoshida Satoya、Fujiuchi Akiyoshi、Ohmi Masashi、Isogai Yumi、Sakaguchi Teruhiro、Eguchi Shunsuke、Tsuda Takuma、Kato Katsuhiro、Ohashi Koji、Ouchi Noriyuki、Park Hyi-Man、Murohara Toyoaki、Takefuji Mikito
    • Journal Title

      Biomedicine & Pharmacotherapy

      Volume: 146 Pages: 112566-112566

    • DOI

      10.1016/j.biopha.2021.112566

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial2022

    • Author(s)
      Shimizu Yuuki、Kondo Kazuhisa、Takashima Shinichiro、Inoue Oto、Usui Soichiro、Takamura MasayukiMitsukawa Nobuyuki、Akita Shinsuke、Ebisawa Soichiro、the TACT-ADRC multicenter trial Group
    • Journal Title

      Angiogenesis

      Volume: 25 Issue: 4 Pages: 535-546

    • DOI

      10.1007/s10456-022-09844-7

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Direct reprogramming of adult adipose-derived regenerative cells toward cardiomyocytes using six transcriptional factors2022

    • Author(s)
      Narita Shingo、Unno Kazumasa、Kato Katsuhiro、Okuno Yusuke、Sato Yoshitaka、Tsumura Yusuke、Fujikawa Yusuke、Shimizu Yuuki、Hayashida Ryo、Kondo Kazuhisa、Shibata Rei、Murohara Toyoaki
    • Journal Title

      iScience

      Volume: 25 Issue: 7 Pages: 104651-104651

    • DOI

      10.1016/j.isci.2022.104651

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hydrogen Sulfide Attenuates Lymphedema Via the Induction of Lymphangiogenesis Through a PI3K/Akt‐Dependent Mechanism2022

    • Author(s)
      Suzuki Junya、Shimizu Yuuki、Hayashi Takumi、Che Yiyang、Pu Zhongyue、Tsuzuki Kazuhito、Narita Shingo、Shibata Rei、Ishii Isao、Calvert John W.、Murohara Toyoaki
    • Journal Title

      Journal of the American Heart Association

      Volume: 11 Issue: 21

    • DOI

      10.1161/jaha.122.026889

    • Related Report
      2022 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 K, Shimizu Y, Suzuki J, Pu Z, Yamaguchi S, Fujikawa Y, Kato K, Ohashi K, Takefuji M, Bando YK, Ouchi N, Calvert JW, Shibata R, Murohara T.
    • Journal Title

      J. Am. Heart Assoc.

      Volume: 17

    • 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] 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] No influence on tumor growth by intramuscular injection of adipose-derived regenerative cells: safety evaluation of therapeutic angiogenesis with cell therapy2021

    • Author(s)
      Suzuki Junya、Shimizu Yuuki、Tsuzuki Kazuhito、Pu Zhongyue、Narita Shingo、Yamaguchi Shukuro、Katagiri Takeshi、Iwata Etsuo、Masutomi Tomohiro、Fujikawa Yusuke、Shibata Rei、Murohara Toyoaki
    • Journal Title

      American Journal of Physiology-Heart and Circulatory Physiology

      Volume: 320 Issue: 1 Pages: 447-457

    • DOI

      10.1152/ajpheart.00564.2020

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Treatment with adipose-derived regenerative cells enhances ischemia-induced angiogenesis via exosomal microRNA delivery in mice2021

    • Author(s)
      Kato T, Kato K, Shimizu Y, Takefuji M, Murohara T.
    • Journal Title

      Nagoya Journal of Medical Science

      Volume: 83 Issue: 3 Pages: 465-476

    • DOI

      10.18999/nagjms.83.3.465

    • NAID

      120007147355

    • ISSN
      0027-7622
    • URL

      https://nagoya.repo.nii.ac.jp/records/2001439

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 心不全病態と細小血管症 糖尿病性心筋症から冠循環不全を考える2024

    • Author(s)
      坂東泰子
    • Organizer
      第88回日本循環器学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Clonal hematopoiesis: A new potential link between cancer and cardiovascular disease2023

    • Author(s)
      Yoshimitsu Yura
    • Organizer
      第87回日本循環器学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Hydrogen Sulfide is a novel therapeutic target for secondary lymphedema2023

    • Author(s)
      Suzuki J, Shimizu Y, Hayashi T, Che Y, Pu Z, Tsuzuki K, Narita S, Shibata R, Ishii I, Calvert JW, Murohara T
    • Organizer
      第87回日本循環器学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 皮下脂肪組織由来間葉系前駆細胞を用いた重症虚血肢に対する血管新生療法:多施設共同研究解析結果2022

    • Author(s)
      清水優樹、柴田玲、室原豊明
    • Organizer
      第50回日本血管外科学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 血管新生における新規標的分子の解析 ー概日リズム障害の影響ー2022

    • Author(s)
      清水優樹、都築一仁、室原豊明
    • Organizer
      第51回日本心脈管作動物質学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Omentin Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E Knockout Mice2021

    • Author(s)
      Fang L, Ohashi K, Takikawa T, Ozaki Y, Takahara K, Murohara T, Ouchi N.
    • Organizer
      American Heart Association Scientific Session 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Diallyl Trisulfide Augments Lymphangiogenesis via an Akt-Dependent Mechanism and Ameliorates Lymphedema2021

    • Author(s)
      Suzuki J, Shimizu Y, Pu Z, Hayashi T, Che Y, Calvert JW, Murohara T.
    • Organizer
      American Heart Association Scientific Session 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of Critical Six Transcriptional Factors for Reprogramming of Mouse Adipose-Derived Regenerative Cells Toward Cardiomyocytes and Its Therapeutic Effect2021

    • Author(s)
      Narita S, Unno K, Shibata R, Kondo K, Shimizu Y, Kato K, Fujikawa Y, Murohara T.
    • Organizer
      American Heart Association Scientific Session 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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