Role of glucagon in diabetic cardiomyopathy and angiogenesis

• Project/Area Number: 18H02805
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Nagoya University
• Principal Investigator: MUROHARA TOYOAKI 名古屋大学, 医学系研究科, 教授 (90299503)
• Co-Investigator(Kenkyū-buntansha): 大内 乗有 名古屋大学, 医学系研究科, 特任教授 (00595514) ; 坂東 泰子 (暮石泰子) 名古屋大学, 医学部附属病院, 講師 (60452190) ; 柴田 玲 名古屋大学, 医学系研究科, 特任教授 (70343689) ; 近藤 和久 名古屋大学, 医学系研究科, 講師 (90644659)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 糖尿病 / 心不全 / インクレチン / GLP-1 / マイオカイン / アディポカイン / 血管新生 / 毛細血管 / グルカゴン / 心機能 / GLP-1受容体 / GLP-1受容体作動薬 / 心血管不全 / 血管内皮機能 / 血管再生 / 細胞内シグナル / 糖尿病性心筋症 / 毛細血管障害

Outline of Final Research Achievements

We studies the role of glucagon and GLP-1 in the regulation of myocardial angiogenesis and diabetic cardiomyopathy.
(1) Using glucagon and GLP-1 knockout mice, we demonstrated that physiological concentration of glucagon can protect against heart failure, while pharmacological high dose of glucagon is harmful to cardiac function (Nishimura et al. manuscript in revise)。
(2) Our group discovered a new myokine called myonectin that is released from the skeletal muscles during exercise. And we showed that myonectin is protective against myocardial ischemia/reperfusion-mediated heart failure. So myonectin can link the mechanism why regular exercise is healthy for cardiovascular disease.

Academic Significance and Societal Importance of the Research Achievements

近年高齢化を背景に心不全や２型糖尿病患者が増加している。糖尿病に心不全が合併すると予後が極めて悪くなることが知られている。糖尿病患者の中には、冠動脈病変が無くとも、心機能が低下している例があり「糖尿病性心筋症」と呼ばれているが、その機序は未だ不明な点が多い。我々は生理的な体内濃度のグルカゴンは心不全に対し保護的に働くこと, 高用量グルカゴンは心臓に対し障害的に働くことを初めて示した。現在インクレチン関連製剤が広く用いられており、我々の研究成果は臨床所見の理解に役立つ。また我々は、マイオカインの発見により、運動が心臓機能に良い影響を与えることの機序の一端を初めて解明することができた。

Research Products

• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic Angiogenesis Using Bone Marrow Mononuclear Cell Transplantation ― A New Standard Treatment for Thromboangiitis Obliterans? ― (2020)
  • Author(s): Shibata Rei、Yamaguchi Shukuro、Murohara Toyoaki
  • Journal Title: Circulation Journal Volume: 84 Issue: 4 Pages: 549-550
  • DOI: 10.1253/circj.CJ-20-0137
  • NAID: 130007815657
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-03-25
  • Peer Reviewed / Open Access
• [Journal Article] Adipolin/C1q/Tnf-related protein 12 prevents adverse cardiac remodeling after myocardial infarction. (2020)
  • Author(s): Takikawa T, Ohashi K, Ogawa H, Otaka N, Kawanishi H, Fang L, Ozaki Y, Eguchi S, Tatsumi M, Takefuji M, Murohara T, Ouchi N.
  • Journal Title: PLoS One. Volume: 15 Issue: 12 Pages: e0243483-e0243483
  • DOI: 10.1371/journal.pone.0243483
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic angiogenesis using autologous adipose-derived regenerative cells in patients with critical limb ischaemia in Japan: a clinical pilot study (2020)
  • Author(s): Katagiri Takeshi、Kondo Kazuhisa、Shibata Rei、Hayashida Ryo、Shintani Satoshi、Yamaguchi Shukuro、Shimizu Yuuki、Unno Kazumasa、Kikuchi Ryosuke、Kodama Akio、Takanari Keisuke、Kamei Yuzuru、Komori Kimihiro、Murohara Toyoaki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 16045-16045
  • DOI: 10.1038/s41598-020-73096-y
  • Peer Reviewed / Open Access
• [Journal Article] C1q/TNF-Related Protein 9 Promotes Revascularization in Response to Ischemia via an eNOS-Dependent Manner (2020)
  • Author(s): Yamaguchi Shukuro、Shibata Rei、Ohashi Koji、Enomoto Takashi、Ogawa Hayato、Otaka Naoya、Hiramatsu-Ito Mizuho、Masutomi Tomohiro、Kawanishi Hiroshi、Murohara Toyoaki、Ouchi Noriyuki
  • Journal Title: Frontiers in Pharmacology Volume: 11 Pages: 1313-1313
  • DOI: 10.3389/fphar.2020.01313
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic Angiogenesis with Somatic Stem Cell Transplantation (2020)
  • Author(s): Murohara Toyoaki
  • Journal Title: Korean Circulation Journal Volume: 50 Issue: 1 Pages: 12-12
  • DOI: 10.4070/kcj.2019.0288
  • Peer Reviewed / Open Access
• [Journal Article] Adipolin/CTRP12 protects against pathological vascular remodeling through suppression of smooth muscle cell growth and macrophage inflammatory response. (2019)
  • Author(s): Ogawa H, Ohashi K, Ito M, Shibata R, Kanemura N, Yuasa D, Kambara T, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Otaka N, Kawanishi H, Yamaguchi S, Enomoto T, Abe T, Kaneko M, Takefuji M, Murohara T, Ouchi N.
  • Journal Title: Cardiovasc Res. Volume: in press Issue: 1 Pages: 237-249
  • DOI: 10.1093/cvr/cvz074
  • Peer Reviewed / Open Access
• [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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Anti-angiogenic isoform of vascular endothelial growth factor-A in cardiovascular and renal disease. (2019)
  • Author(s): Kikuchi R, Stevens M, Harada K, Oltean S, Murohara T.
  • Journal Title: Adv. Clin. Chem. Volume: 88 Pages: 1-33
  • DOI: 10.1016/bs.acc.2018.10.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between the ratio of anti-angiogenic isoform of VEGF-A to total VEGF-A and adverse clinical outcomes in patients after acute myocardial infarction. (2018)
  • Author(s): Harada K, Kikuchi R, Ishii H, Shibata Y, Suzuki S, Tanaka A, Suzuki A, Hirayama K, Murohara T.
  • Journal Title: Int. J. Cardiol. Heart Vasc. Volume: 19 Pages: 3-7
  • DOI: 10.1016/j.ijcha.2018.03.004
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Lymphangiogenesis on Cardiac Remodeling After Ischemia and Reperfusion Injury. (2018)
  • Author(s): Shimizu Y, Polavarapu R, Eskla KL, Pantner Y, Nicholson CK, Ishii M, Brunnhoelzl D, Mauria R, Husain A, Naqvi N, Murohara T, Calvert JW.
  • Journal Title: J Am Heart Assoc. Volume: 7 Issue: 19
  • DOI: 10.1161/jaha.118.009565
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury. (2018)
  • Author(s): Otaka N, Shibata R, Ohashi K, Uemura Y, Kambara T, Enomoto T, Ogawa H, Ito M, Kawanishi H, Maruyama S, Joki Y, Fujikawa Y, Narita S, Unno K, Kawamoto Y, Murate T, Murohara T, Ouchi N.
  • Journal Title: Circ Res. Volume: 123 Issue: 12 Pages: 1326-1338
  • DOI: 10.1161/circresaha.118.313777
  • Peer Reviewed
• [Presentation] Clathrin-mediated Endocytosis Plays a Key Role in Stem Cell Therapy for Ischemic Heart Disease (2020)
  • Author(s): Shunsuke Eguchi, Mikito Takefuji, Toyoaki Murohara
  • Organizer: American Heart Association (AHA)
  • Int'l Joint Research
• [Presentation] Impact of Circadian Rhythm Disorders on Reparative Angiogenesis (2020)
  • Author(s): Kazuhito Tsuzuki, Yuuki Shimizu, Zhongyue Pu, Junya Suzuki, Shukuro Yamaguchi, Rei Shibata, Toyoaki Murohara
  • Organizer: American Heart Association (AHA)
  • Int'l Joint Research
• [Presentation] Safety Evaluation of Therapeutic Angiogenesis With Adipose-derived Regenerative Cells for Ischemic Limb in a Tumor Bearing Model (2020)
  • Author(s): Junya Suzuki, Yuuki Shimizu, Kazuhito Tsuzuki, Zhongyue Pu, Shukuro Yamaguchi, Rei Shibata, Toyoaki Murohara
  • Organizer: American Heart Association (AHA)
  • Int'l Joint Research
• [Presentation] Glucose-dependent insulinotropic peptide is essential for maintenance of cardiac lipid metabolism via FGF21-dependent pathway (2019)
  • Author(s): Y Remina, Y Kureishi Bando, R Ozaki, T Kamihara, K Nishimura, T Murohara
  • Organizer: 欧州心臓病学会
  • Int'l Joint Research
• [Presentation] C1q/Tumor Necrosis Factor-Related Protein 9 Stimulates Revascularization in Response to Ischemia Through an Endothelial Nitric Oxide Synthase-Dependent Pathway (2019)
  • Author(s): Shukuro Yamaguchi ,Rei Shibata ,Koji Ohashi ,Toyoaki Murohara, Noriyuki Ouchi
  • Organizer: アメリカ心臓協会年次集会
  • Int'l Joint Research
• [Presentation] Implantation of Adipose-Derived Regenerative Cells Promotes Coordinated Angiogenesis and Lymphangiogenesis in Reparative Hind Limb Ischemia Model (2019)
  • Author(s): Zhongyue Pu ,Yuuki Shimizu ,Kazuhito Tsuzuki ,Junya Suzuki, Toyoaki Murohara
  • Organizer: アメリカ心臓協会年次集会
  • Int'l Joint Research
• [Presentation] Impaired Autophagic Off-rate is Responsible for Cardiac Aging via Oxidative Stress (2019)
  • Author(s): Yasuko K Bando ,Takahiro Kamihara ,Kazuyuki Nishimura ,Yasheng Retina, Toyoaki Murohara
  • Organizer: アメリカ心臓協会年次集会
  • Int'l Joint Research
• [Presentation] Glucagon acts as a guardian of the heart against catecholamine elevation. (2019)
  • Author(s): 西村和之、板東泰子、室原豊明 他
  • Organizer: 第83回日本循環器学会総会
• [Presentation] Glucose metabolism in failing hearts. (2019)
  • Author(s): Toyoaki Murohara
  • Organizer: International Society of Heart Research, Beijing World Congress XXIII
  • Int'l Joint Research / Invited
• [Presentation] Lymphangiogenesis contributes to the ischemia induced angiogenesis in HLI via clearance of inflammation. (2019)
  • Author(s): Zhongyue Pu, Yuuki Shimizu, Toyoaki Murohara
  • Organizer: 第83回日本循環器学会総会
• [Presentation] C1q/TNF-related protein 9 enhances ischemia-induced revascularization through an eNOS-dependent pathway (2019)
  • Author(s): 山口淑郎，柴田玲，大橋浩二，室原豊明，大内乗有
  • Organizer: 第83回日本循環器学会総会
• [Presentation] Glucagon acts as a guardian of the heart against catecholamine surge. (2018)
  • Author(s): Kazuyuki Nishimura, Yasuko Bando, Takatoshi Kamihara, Remina Yasheng, Toyoaki Murohara
  • Organizer: European Society of Cardiology, Congress 2018
  • Int'l Joint Research