Effects of Rikkunshito on upstream therapy for atrial fibrillation through a ghrelin signaling

• Project/Area Number: 17K09308
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Oita University
• Principal Investigator: Nakagawa Mikiko 大分大学, 医学部, 教授 (50244182)
• Co-Investigator(Kenkyū-buntansha): 安部 一太郎 大分大学, 医学部, 病院特任助教 (00747595)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 六君子湯 / グレリン / 心房細動 / 心房筋線維化 / 漢方薬 / 循環器・高血圧 / 生理学

Outline of Final Research Achievements

Atrial fibrillation (AF) is a frequent arrhythmia that is associated with morbidity and mortality. Ghrelin is an acylated peptide hormone secreted by the stomach and includes stimulation of growth hormone secretion and inhibition of inflammation and apoptosis in the hearts. These observations led to a hypothesis that potentiation of ghrelin signaling can attenuate angiotensin II (AngII)-induced AF. Rikkunshito (RKT) is a traditional herbal medicine widely used in patients with gastrointestinal symptoms. It has been reported that RKT potentiates ghrelin signaling and exert anti-inflammatory and anti-fibrotic effects in several organs. This study tested the hypothesis that RKT can suppress AngII-induced inflammatory atrial fibrosis and ameliorate enhanced vulnerability to AF. Our results demonstrated that RKT suppresses atrial inflammatory fibrosis and enhances AF vulnerability in mice induced by continuous subcutaneous AngII infusion by potentiating the GHSR-Sirt1 pathway.

Academic Significance and Societal Importance of the Research Achievements

心房細動は発生頻度の高い不整脈であり心原性脳梗塞の原因となるため、その予防法の開発は重要な課題である。消化管に働くペプチドホルモンのグレリンが、心臓においては心房の炎症や線維化を抑制し、心房細動の発症を抑制する可能性が示唆されている。漢方薬の六君子湯はグレリン分泌薬であり、胃薬として広く使用されている。本研究では、六君子湯に心房筋の線維化を抑制し、心房細動の発症を抑制する効果があることを世界で初めて立証した。六君子湯は心房細動の予防薬として、健康長寿を実現する手段の一つとなり得る可能性が示唆される。

Research Products

• [Journal Article] A traditional herbal medicine rikkunshito prevents angiotensin II-Induced atrial fibrosis and fibrillation (2020)
  • Author(s): Zhan Yinge、Abe Ichitaro、Nakagawa Mikiko、Ishii Yumi、Kira Shintaro、Miyoshi Miho、Oniki Takahiro、Kondo Hidekazu、Teshima Yasushi、Yufu Kunio、Arakane Motoki、Daa Tsutomu、Takahashi Naohiko
  • Journal Title: Journal of Cardiology Volume: 76 Issue: 6 Pages: 626-635
  • DOI: 10.1016/j.jjcc.2020.07.001
  • Peer Reviewed
• [Presentation] Rikkunshito, a Traditional Japanese Medicine, Prevented Angiotensin II Induced Atrial Remodeling and Fibrillation (2019)
  • Author(s): I Abe, Z Yinge, M Nakagawa, Y Teshima,T Tanino, T Harada, K Mitarai, K Kawano, Y Ishii, S Yoshimura, MMiyoshi, S Kira, T Oniki, Y Ikebe, R Ayabe, S Saito, H Kondo, A Fukui, H Okada, H Akioka, T Shinohara, K Yufu, T Takahashi
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Rikkunshito, a Traditional Japanese Medicine, Prevented Angiotensin II Induced Atrial Remodeling and Fibrillation (2018)
  • Author(s): I Abe, Z Yinge, M Nakagawa, Y Teshima,T Tanino, T Harada, K Mitarai, K Kawano, Y Ishii, S Yoshimura, MMiyoshi, S Kira, T Oniki, Y Ikebe, R Ayabe, S Saito, H Kondo, A Fukui, H Okada, H Akioka, T Shinohara, K Yufu, T Takahashi
  • Organizer: 第65回日本不整脈心電学会学術集会
• [Presentation] 六君子湯の心房線維化と心房細動抑制効果－アンギオテンシンⅡ負荷モデルマウスを用いて－ (2018)
  • Author(s): 中川幹子、安部一太郎、Zhan Yinge、手嶋泰之、高橋尚彦
  • Organizer: 日本東洋医学会 大分県部会
• [Presentation] Rikkunshito, a Traditional Japanese Medicine, Prevented Angiotensin II Induced Atrial Remodeling and Fibrillation (2018)
  • Author(s): Ichitaro Abe, Zhan Yinge, Mikiko Nakagawa, Yasushi Teshima,T Tanino, T Harada, K Mitarai, K Kawano, Y Ishii, S Yoshimura, M Fujinami, M Miyoshi, S Kira, T Oniki, Y Ikebe,R Ayabe, S Saito, H Kondo, A Fukui, H Okada, H Akioka, T Shinohara, K Yufu, Naohiko Takahashi
  • Organizer: 第82回日本循環器学会学術集会