Targetting ryanodine receptors for anti-heart failure and anti-arrhythmic therapy

• Project/Area Number: 18K08039
• 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: Yamaguchi University
• Principal Investigator: Kobayashi Shigeki 山口大学, 大学院医学系研究科, 准教授 (90397993)
• Co-Investigator(Kenkyū-buntansha): 矢野 雅文 山口大学, 大学院医学系研究科, 教授 (90294628) ; 山本 健 山口大学, 大学院医学系研究科, 教授 (50363122)
• Project Period (FY): 2018-04-01 – 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 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: リアノジン受容体 / 心不全 / 致死的不整脈致死的不整脈 / ダントロレン / 心室頻拍 / カルシウムハンドリング / 悪性高熱症 / 不整脈

Outline of Final Research Achievements

The purpose of this study is to develop a therapeutic method targeting RyR2 and apply it to clinical practice in patients with chronic heart failure and fatal arrhythmia. In a clinical study, a multicenter randomized double-blind study (SHO-IN Trial: UMIN 28766) was started to evaluate the prognosis and effect and safety of dantrolene on chronic heart failure and ventricular arrhythmia, and is currently underway. In basic research, we demonstrated the molecular mechanism of action and efficacy of RyR2 targeted therapy in vitro and in vivo using a mouse transverse coarctation (TAC) model and a mouse myocardial infarction (MI) model.

Academic Significance and Societal Importance of the Research Achievements

心臓型リアノジン受容体（RyR2)を標的としたダントロレンによる心不全・不整脈の新たな治療法がさまざまな基礎疾患を有する慢性心不全に対して有効かどうかを実証することを目的としている。ダントロレンのRyR2に対する新たな分子学的作用機序提唱から、動物実験レベルでダントロレンの抗心不全効果・抗不整脈効果を証明しており、極めて斬新かつ独創的である。ダントロレンは、悪性高熱症や全身こむら返り、痙性麻痺に保険適応が有り、薬物の安全性に関しては実証されているため、本研究で、有効性が実証されれば医療費の抑制にもつながり社会的貢献度は大である。また、RyR2を標的とした新たな創薬へと繋がっていくと考えられる。

Research Products

• [Journal Article] Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease (2021)
  • Author(s): Nakamura Yoshihide、Yamamoto Takeshi、Xu Xiaojuan、Kobayashi Shigeki、Tanaka Shinji、Tamitani Masaki、Saito Takashi、Saido Takaomi C.、Yano Masafumi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 7289-7289
  • DOI: 10.1038/s41598-021-86822-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling (2020)
  • Author(s): Kohno Michiaki、Kobayashi Shigeki、Yamamoto Takeshi、Yoshitomi Ryosuke、Kajii Toshiro、Fujii Shohei、Nakamura Yoshihide、Kato Takayoshi、Uchinoumi Hitoshi、Oda Tetsuro、Okuda Shinichi、Watanabe Kenji、Mizukami Yoichi、Yano Masafumi
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 714-714
  • DOI: 10.1038/s42003-020-01443-w
  • Peer Reviewed / Open Access
• [Journal Article] Dantrolene prevents hepatic steatosis by reducing cytoplasmic Ca 2+ level and ER stress (2020)
  • Author(s): Tamitani M, Yamamoto T, Yamamoto N, Fujisawa K, Tanaka S, Nakamura Y, Uchinoumi H, Oda T, Okuda S, Takami T, Kobayashi S, Sakaida I, Yano M.
  • Journal Title: Biochem Biophys Rep. Volume: 23:100787. Pages: 100787-100793
  • DOI: 10.1016/j.bbrep.2020.100787
  • Peer Reviewed / Open Access
• [Journal Article] Author's reply: The RyR2 : Targeting therapy against lethal arrhythmia (2020)
  • Author(s): Kobayashi Shigeki、Yoshiga Yasuhiro、Yano Masafumi
  • Journal Title: Journal of Cardiology Volume: in press Issue: 3 Pages: 1-2
  • DOI: 10.1016/j.jjcc.2020.03.011
  • Peer Reviewed / Open Access
• [Journal Article] Stabilizing cardiac ryanodine receptor prevents the development of cardiac dysfunction and lethal arrhythmia in Ca2+/calmodulin-dependent protein kinase IIδc transgenic mice (2020)
  • Author(s): Sufu-Shimizu Yoko、Okuda Shinichi、Kato Takayoshi、Nishimura Shigehiko、Uchinoumi Hitoshi、Oda Tetsuro、Kobayashi Shigeki、Yamamoto Takeshi、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 524 Issue: 2 Pages: 431-438
  • DOI: 10.1016/j.bbrc.2020.01.107
  • Peer Reviewed / Open Access
• [Journal Article] G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model (2020)
  • Author(s): Hamada Yoriomi、Yamamoto Takeshi、Nakamura Yoshihide、Sufu-Shimizu Yoko、Nanno Takuma、Fukuda Masakazu、Ono Makoto、Oda Tesuro、Okuda Shinichi、Ueyama Takeshi、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 21 Pages: 100711-100711
  • DOI: 10.1016/j.bbrep.2019.100711
  • Peer Reviewed / Open Access
• [Journal Article] A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design (2020)
  • Author(s): Kobayashi Shigeki, Yano Masafumi et al.
  • Journal Title: Journal of Cardiology Volume: 75 Issue: 4 Pages: 454-461
  • DOI: 10.1016/j.jjcc.2019.08.020
  • Peer Reviewed
• [Journal Article] Dantrolene prevents ventricular tachycardia by stabilizing the ryanodine receptor in pressure- overload induced failing hearts (2020)
  • Author(s): Kajii Toshiro、Kobayashi Shigeki、Shiba Sho、Fujii Shohei、Tamitani Masaki、Kohno Michiaki、Nakamura Yoshihide、Nanno Takuma、Kato Takayoshi、Okuda Shinichi、Uchinoumi Hitoshi、Oda Tetsuro、Yamamoto Takeshi、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 521 Issue: 1 Pages: 57-63
  • DOI: 10.1016/j.bbrc.2019.10.071
  • Peer Reviewed / Open Access
• [Journal Article] Ryanodine receptor-bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia (2019)
  • Author(s): Nakamura Yoshihide、Yamamoto Takeshi、Kobayashi Shigeki、Tamitani Masaki、Hamada Yoriomi、Fukui Go、Xu Xiaojuan、Nishimura Shigehiko、Kato Takayoshi、Uchinoumi Hitoshi、Oda Tetsuro、Okuda Shinichi、Yano Masafumi
  • Journal Title: JCI Insight Volume: 4 Issue: 11 Pages: 1-18
  • DOI: 10.1172/jci.insight.126112
  • Peer Reviewed / Open Access
• [Journal Article] Addition of a β1-Blocker to Milrinone Treatment Improves Cardiac Function in Patients with Acute Heart Failure and Rapid Atrial Fibrillation (2019)
  • Author(s): Kobayashi Shigeki、Myoren Takeki、Kajii Toshiro、Kohno Michiaki、Nanno Takuma、Ishiguchi Hironori、Nishimura Shigehiko、Fukuda Masakazu、Hino Akihiro、Fujimura Tatsuhiro、Ono Makoto、Uchinoumi Hitoshi、Tateishi Hiroki、Mochizuki Mamoru、Oda Tetsuro、Okuda Shinichi、Yoshiga Yasuhiro、Kawano Reo、Yano Masafumi
  • Journal Title: Cardiology Volume: 142 Issue: 4 Pages: 195-202
  • DOI: 10.1159/000499400
  • Peer Reviewed / Open Access
• [Journal Article] Localized Doxorubicin-Induced Cardiomyopathy Complicated With Shower Emboli Originating From Apical Intramural Thrombi (2018)
  • Author(s): Ishiguchi H, Kobayashi S, Okuda S, Okamura T, Okada M, Takemura G, Takahashi M, Mikamo A, Hamano K, Yano M.
  • Journal Title: Circulation Journal Volume: 82 Issue: 9 Pages: 2375-2376
  • DOI: 10.1253/circj.CJ-17-1231
  • NAID: 130007438912
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-08-24
  • Peer Reviewed
• [Journal Article] Treatment of Class IV Lupus Nephritis with Mycophenolate Mofetil Monotherapy (2018)
  • Author(s): Nawata Takashi、Kubo Makoto、Fujii Shohei、Shiragami Kosaku、Ikegami Tadayoshi、Kobayashi Shigeki、Hisano Satoshi、Yano Masafumi
  • Journal Title: Internal Medicine Volume: 57 Issue: 14 Pages: 2067-2070
  • DOI: 10.2169/internalmedicine.0304-17
  • NAID: 130007404877
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-07-15
  • Peer Reviewed
• [Journal Article] Nuclear translocation of calmodulin in pathological cardiac hypertrophy originates from ryanodine receptor bound calmodulin (2018)
  • Author(s): Oda Tetsuro、Yamamoto Takeshi、Kato Takayoshi、Uchinoumi Hitoshi、Fukui Go、Hamada Yoriomi、Nanno Takuma、Ishiguchi Hironori、Nakamura Yoshihide、Okamoto Yoko、Kono Michiaki、Okuda Shinichi、Kobayashi Shigeki、Bers Donald M.、Yano Masafumi
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 125 Pages: 87-97
  • DOI: 10.1016/j.yjmcc.2018.10.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Change in muscle volume after steroid therapy in patients with myositis assessed using cross-sectional computed tomography. (2018)
  • Author(s): Nawata T, Kubo M, Nomura T, Oishi K, Shiragami K, Ikegami T, Okada M, Kobayashi S, Yano M
  • Journal Title: BMC Musculoskelet Disord Volume: 19 Issue: 1 Pages: 93-93
  • DOI: 10.1186/s12891-018-2008-8
  • Peer Reviewed / Open Access
• [Journal Article] Strict sequential catheter ablation strategy targeting the pulmonary veins and superior vena cava for persistent atrial fibrillation. (2018)
  • Author(s): Yoshiga Y, Shimizu A, Ueyama T, Ono M, Fukuda M, Fumimoto T, Ishiguchi H, Omuro T, Kobayashi S, Yano M.
  • Journal Title: J Cardiol Volume: in press Issue: 2 Pages: 128-134
  • DOI: 10.1016/j.jjcc.2018.01.004
  • Peer Reviewed
• [Journal Article] Mutation-linked, excessively tight interaction between the calmodulin binding domain and the C-terminal domain of the cardiac ryanodine receptor as a novel cause of catecholaminergic polymorphic ventricular tachycardia. (2018)
  • Author(s): Nishimura S, Yamamoto T, Nakamura Y, Kohno M, Hamada Y, Sufu Y, Fukui G, Nanno T, Ishiguchi H, Kato T, Xu X, Ono M, Oda T, Okuda S, Kobayashi S, Yano M.
  • Journal Title: Heart Rhythm Volume: 印刷中 Issue: 6 Pages: 905-914
  • DOI: 10.1016/j.hrthm.2018.02.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca 2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy (2018)
  • Author(s): Okuda Shinichi、Sufu-Shimizu Yoko、Kato Takayoshi、Fukuda Masakazu、Nishimura Shigehiko、Oda Tetsuro、Kobayashi Shigeki、Yamamoto Takeshi、Morimoto Sachio、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 496 Issue: 4 Pages: 1250-1256
  • DOI: 10.1016/j.bbrc.2018.01.181
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Sterile Inflammation through Ca2+ Calmodulin-Dependent Protein Kinase II is Essential for Adverse Cardiac Remodeling (2021)
  • Author(s): 末冨 建、奥田真一、岡本陽子、楯田聡美、河野通暁、梶井俊郎、内海仁志、小田哲郎、小林茂樹、山本 健、矢野雅文
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] Dantrolene prevents right ventricular remodeling and ventricular tachycardia in pulmonary artery hypertension (2021)
  • Author(s): Shinji Tanaka, Takeshi Yamamoto, Junya Nawata, Shohei Fujii, Yoshihide Nakamura, Michiaki Kohno, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 第37回国際心臓研究学会日本部会
• [Presentation] Anti-inflammatory approach for heart failure targeting Calcium-Calmodulin dependent protein kinase (2020)
  • Author(s): Takeshi Suetomi, Michiaki Kono, Toshiro Kajii, Masaki Tamitani, Yoshihide Nakamura, Takayoshi Kato, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] Arrhythmia Treatment Targeting Ryanodine receptor (2019)
  • Author(s): Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: The 66th Annual Meeting of the Japanese Heart Rhythm Sociaty
  • Int'l Joint Research / Invited
• [Presentation] リアノジン受容体を分子標的とした心不全・不整脈治療 (2019)
  • Author(s): 小林茂樹、山本健、矢野雅文
  • Organizer: 第４０回日本循環制御医学会
  • Invited
• [Presentation] カルシウム制御による心不全治療戦略 ―リアノジン受容体安定化治療の可能性について― (2018)
  • Author(s): 小林茂樹
  • Organizer: 第22回日本心不全学会
  • Invited
• [Book] 循環代謝ー原始・現代・未来ー (2020)
  • Author(s): 小林茂樹、矢野雅文
  • Total Pages: 142
  • Publisher: 北隆館
• [Book] メディカル・サイエンス・ダイジェスト 心不全 Up to Date (2019)
  • Author(s): 小林茂樹、矢野雅文
  • Total Pages: 57
  • Publisher: ニューサイエンス社
• [Book] Cutting Edge of Molecular Cardiology 新しい臨床を開拓するための分子循環器病学 (2019)
  • Author(s): 小林茂樹
  • Total Pages: 210
  • Publisher: 南山堂
  • ISBN: 9784525249410