Elucidation of the effect of Midkine on myocardial injury and protection and development of novel heart failure therapy

• Project/Area Number: 18K08025
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamagata University
• Principal Investigator: Shishido Tetsuro 山形大学, 医学部, 非常勤講師 (60400545)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: midkine / nucleolin / 心不全 / 心腎連関 / 低酸素 / 腎臓病 / 心肥大

Outline of Final Research Achievements

Chronic kidney disease and chronic pulmonary disease are risk factors for heart failure. Organ hypoperfusion and hypoxia produce midkine (MK) in the lungs and kidneys, and circulating MK is responsible for the exacerbation of heart failure. On the other hand, MK reportedly has a role as a cardioprotective agent. In this study, we focus on Nucleolin, a nuclear protein that binds to MK, to elucidate two mechanisms: 1) how MK increases epidermal growth factor receptor (EGFR) activity and activates cardiac hypertrophy via surface Nucleolin, and 2) the anti-apoptotic effect of Nucleolin, which binds to MK and enters the nucleus. We analyze hearts after transverse aortic stenosis using heart-specific MK overexpressing mice and GAR domain-deficient Nucleolin heart-specific overexpressing mice to clarify the role of MK on cardiac function.

Academic Significance and Societal Importance of the Research Achievements

我々は、Midkine (MK)がEGFRを活性化し左室リモデリングの進展を促すことを報告したが、詳細な機序は不明であった。加えて、MKとNucleolinとの結合によって、EGFR活性が亢進することや左室リモデリングが進展することを明らかにした報告は皆無である。また、NucleolinがMKと結合後に核内に移行するが、核内Nucleolinによる抗アポトーシス効果やMKとの関連性に関しては、報告がない。本研究ではMKとNucleolin複合体が心筋細胞障害、心筋細胞保護のdual effectを発揮する機序に関して理解が深まるため、心不全の新規の治療法の開発につながる重要な基盤研究となる。

Research Products

• [Int'l Joint Research] University of Texas/MD Anderson Cancer Center(米国)
• [Int'l Joint Research] Yeungnam University/Department of Pharmacology,/College of Medicine(韓国)
• [Journal Article] The association between microRNA-21 and hypertension-induced cardiac remodeling. (2020)
  • Author(s): Watanabe K, Watanabe T, Otaki Y, Shishido T, Kato S, Tamura H, S. Nishiyama S, Takahashi H, Arimoto T, Watanabe M
  • Journal Title: PLoS One. Volume: 15 Issue: 2 Pages: e0226053-e0226053
  • DOI: 10.1371/journal.pone.0226053
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Impaired Pancreatic β-Cell Function on Cardiovascular Prognosis in Heart Failure Patients Without Diabetes Mellitus (2019)
  • Author(s): Narumi T, Watanabe T, Kato S, Tamura H, Nishiyama S, Takahashi H, Arimoto T, Shishido T, Watanabe M
  • Journal Title: Circulation Reports Volume: 1 Issue: 6 Pages: 255-260
  • DOI: 10.1253/circrep.CR-19-0033
  • NAID: 130007662190
  • ISSN: 2434-0790
  • Year and Date: 2019-06-10
  • Peer Reviewed
• [Journal Article] Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting DNA Damage Response (2019)
  • Author(s): Tetsuya Takahashi, Tetsuro Shishido, Daisuke Kinoshita, Ken Watanabe, Taku Toshima, Takayuki Sugai, Taro Narumi, Yoichiro Otaki, Harutoshi Tamura, Satoshi Nishiyama, Takanori Arimoto, Hiroki Takahashi, Takuya Miyamoto, Tetsu Watanabe, Chang-Hoon Woo, Jun-ichi Abe, Yasuchika Takeishi, Isao Kubota and Masafumi Watanabe
  • Journal Title: JACC: Basic to Translational Science Volume: 4 Issue: 2 Pages: 234-234
  • DOI: 10.1016/j.jacbts.2018.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ventricular wall stress and silent myocardial damage are associated with pulse pressure in the general population. (2018)
  • Author(s): Takahashi T, Shishido T, Watanabe K, Sugai T, Toshima T, Kinoshita D, Yokoyama M, Tamura H, Nishiyama S, Takahashi H, Arimoto T, Miyamoto T, Watanabe T, Shibata Y, Konta T, Ueno Y, Kato T, Kayama T, Kubota I, Watanabe M.
  • Journal Title: J Clin Hypertens (Greenwich). Volume: 33 Issue: 9 Pages: 1319-1326
  • DOI: 10.1111/jch.13349
  • Peer Reviewed / Open Access
• [Presentation] levated plasma xanthine oxidoreductase activity predicts cardiovascular events in patients with heart failure with preserved ejection fraction (2019)
  • Author(s): Watanabe K, Watanabe T, Otaki Y, Shishido T, Kato S, Tamura H, S. Nishiyama S, Takahashi H, Arimoto T, Watanabe M
  • Organizer: ESC
  • Int'l Joint Research
• [Presentation] Cardiac nuclear higt-mobility grop box 1 attenuates angiotesin Ⅱinduced pathological cardiac hypertrophy by inhibitting DAN damage response pathway. (2018)
  • Author(s): T.Takahashi
  • Organizer: ESC, Munich；2018.8
  • Int'l Joint Research