Role of the novel myokine myonectin in regulation of ischemic heart disease

• Project/Area Number: 17H04175
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagoya University
• Principal Investigator: OUCHI Noriyuki 名古屋大学, 医学系研究科, 寄附講座教授 (00595514)
• Co-Investigator(Kenkyū-buntansha): 大橋 浩二 名古屋大学, 医学系研究科, 寄附講座講師 (10595515) ; 柴田 玲 名古屋大学, 医学系研究科, 寄附講座教授 (70343689) ; 室原 豊明 名古屋大学, 医学系研究科, 教授 (90299503)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 虚血性心疾患 / 循環器・高血圧 / 運動 / 運動療法

Outline of Final Research Achievements

Here we investigated the role of the exercise-induced myokine myonectin in regulation of ischemic heart disease. We found that myonectin knockout mice had increased myocardial infarct size and reduced cardiac function following ischemia-reperfusion compared with control mice, which were accompanied by enhanced apoptosis and inflammatory response in ischemic heart. In contrast, myonectin transgenic mice had reduced ischemia reperfusion injury compared with control mice. Furthermore, myonectin prevented myocardial ischemic injury by reducing cardiomyocyte apoptosis and macrophage inflammatory response through its ability to promote the sphingosine-1-phosphate/cyclicAMP/Akt signaling pathway. Thus, myonectin can function as an exercise-induced myokine which provides cardioprotection.

Academic Significance and Societal Importance of the Research Achievements

我が国において虚血性心疾患を代表とする心血管病の病態解明及び治療法の確立は最重要課題である。本研究において、運動誘発性の骨格筋由来分泌因子「マイオカイン」であるマイオネクチンが心筋細胞のアポトーシスとマクロファージの炎症反応の抑制を介して心筋虚血再灌流障害を改善することが明らかとなった。従って、マイオネクチンは心筋保護作用を有するマイオカインでありマイオネクチンを標的とした心血管病の創薬開発が期待される。

Research Products

• [Journal Article] Associations among circulating levels of follistatin-like 1, clinical parameters, and cardiovascular events in patients undergoing elective percutaneous coronary intervention with drug-eluting stents (2019)
  • Author(s): Aikawa Tatsuro、Shimada Kazunori、Miyauchi Katsumi、Miyazaki Tetsuro、Sai Eiryu、Ouchi Shohei、Kadoguchi Tomoyasu、Kunimoto Mitsuhiro、Joki Yusuke、Dohi Tomotaka、Okazaki Shinya、Isoda Kikuo、Ohashi Koji、Murohara Toyoaki、Ouchi Noriyuki、Daida Hiroyuki
  • Journal Title: PLOS ONE Volume: 14 Issue: 4 Pages: e0216297-e0216297
  • DOI: 10.1371/journal.pone.0216297
  • Peer Reviewed / Open Access
• [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] 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] 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] 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] 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
• [Journal Article] Role of Adipokines in Cardiovascular Disease (2017)
  • Author(s): Lau WB, Ohashi K, Wang Y, Ogawa H, Murohara T, Ma XL, Ouchi N
  • Journal Title: Circulation Journal Volume: 81 Issue: 7 Pages: 920-928
  • DOI: 10.1253/circj.CJ-17-0458
  • NAID: 130006887060
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chronic psychological stress accelerates vascular senescence and impairs ischemia-induced neovascularization: The role of dipeptidyl peptidase-4/glucagon-like peptide-1-adiponectin axis. (2017)
  • Author(s): Piao L, Zhao G, Zhu E, Inoue A, Shibata R, Lei Y, Hu L, Yu C, Yang G, Wu H, Xu W, Okumura K, Ouchi N, Murohara T, Kuzuya M, ＊Cheng XW.
  • Journal Title: Journal of the American Heart Association. Volume: 6 Issue: 10
  • DOI: 10.1161/jaha.117.006421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Adipolin/C1q/Tnf-related protein 12 attenuates adverse cardiac remodeling in a mouse model of myocardial infarction. (2019)
  • Author(s): Tomonobu Takikawa, Koji Ohashi, Lixin Fang, Hiroshi Kawanishi, Naoya Otaka, Hayato Ogawa, Toyoaki Murohara, Noriyuki Ouchi
  • Organizer: ESC Congress 2019
  • Int'l Joint Research
• [Presentation] 運動誘発性マイオカイン「マイオネクチン」の虚血性心疾患における役割 (2019)
  • Author(s): 大内乗有 大高直也 室原豊明
  • Organizer: 第51回日本動脈硬化学会総会・学術集会
• [Presentation] アディポサイトカイン「アディポリン」の心血管病における役割 (2018)
  • Author(s): 大内乗有、大橋浩二、室原豊明
  • Organizer: 第50回日本動脈硬化学会総会・学術集会
• [Presentation] Role of the adiponectin paralogs C1q/TNF-related proteins in cardiovascular disease. (2018)
  • Author(s): 大内乗有
  • Organizer: 6th Seoul International Congress of Endocrinology and Metabolism (SICEM 2018)
  • Int'l Joint Research / Invited
• [Presentation] Role of the novel adipokine in cardiovascular disease. (2018)
  • Author(s): 大内乗有
  • Organizer: International Academy of Cardiology, Annual Scientific Sessions 2018, 23rd World Congress on Heart Disease
  • Int'l Joint Research / Invited
• [Presentation] アディポネクチンパラログの心血管病における役割 (2017)
  • Author(s): 大内乗有、大橋浩二、柴田玲、小川隼人、室原豊明
  • Organizer: 第38回日本肥満学会
  • Invited
• [Presentation] Role of the adipokine omentin in cardiovascular disease. (2017)
  • Author(s): 大内乗有
  • Organizer: International Academy of Cardiology, Annual Scientific Sessions 2017, 22nd World Congress on Heart Disease
  • Int'l Joint Research / Invited
• [Presentation] Role of the novel adipocytokines in cardiovascular disease. (2017)
  • Author(s): 大内乗有
  • Organizer: 2017 International Congress on Obesity and Metabolic Syndrome in conjunction with the 47th Annual Scientific Meeting of the KSSO
  • Int'l Joint Research / Invited