Ryanodine receptor-targeting therapy for heart failure and lethal arrhythmia

• Project/Area Number: 15K09142
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• 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): 山本 健 山口大学, 大学院医学系研究科, 教授 (50363122) ; 矢野 雅文 山口大学, 大学院医学系研究科, 教授 (90294628)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ryanodine receptor / heart failure / arrhythmia / dantrolene / リアノジン受容体 / 心不全 / 心室頻拍 / カルシウムハンドリング / ダントロレン / 拡張不全 / 高血圧 / 弛緩障害

Outline of Final Research Achievements

We investigated (1) whether transverse aortic constriction (TAC)-induced pressure overload caused Ca2+ leak through cardiac ryanodine receptor (RyR2), and (2) whether chronic administration of dantrolene, a RyR2 stabilizer, inhibited the cardiomyocyte hypertyrophy and dysfunction by stopping the Ca2+leak.The aberrant Ca2+ leak through RyR2 was observed even in the compensated pressure-overloaded heart. Dantrolene restores the cardiomyocyte dysfunction and inhibits the cardiomyocyte hypertrophy by inhibiting the aberrant Ca2+ leak through RyR2. Targeting RyR2 treatment by dantrolene may be a novel strategy for pressure-overloaded hypertrophy.

Research Products

• [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
• [Journal Article] Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure. (2017)
  • Author(s): Kato T, Yamamoto T, Nakamura Y, Nanno T, Fukui G, Sufu Y, Hamada Y, Maeda T, Nishimura S, Ishiguchi H, Murakami W, Fukuda M, Xu X, Hino A, Ono M, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M.
  • Journal Title: Heart Rhythm Volume: 14 Issue: 1 Pages: 120-127
  • DOI: 10.1016/j.hrthm.2016.10.019
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An oxidative stress biomarker, urinary 8-hydroxy-2'-deoxyguanosine, predicts cardiovascular-related death after steroid therapy for patients with active cardiac sarcoidosis. (2016)
  • Author(s): Myoren T, Kobayashi S, Oda S, Nanno T, Ishiguchi H, Murakami W, Okuda S, Okada M, Takemura G, Suga K, Matsuzaki M, Yano M.
  • Journal Title: Int J Cardiol Volume: 17 Pages: 206-213
  • DOI: 10.1016/j.ijcard.2016.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship between the myocardial oxidative stress and cardiac sympathetic hyperactivity in patients with takotsubo cardiomyopathy. (2016)
  • Author(s): Seiko Oda, Shigeki Kobayashi, Takuma Nanno, Hironori Ishiguchi, Takeki Myoren, Wakako Murakami, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Jutaro Yamada, Takayuki Okamura, Masunori Matsuzaki, Masafumi Yano.
  • Journal Title: Bulltin of the Yamaguchi Medical School Volume: 63 Pages: 5-16
  • NAID: 120005842748
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recombinant Atrial Natriuretic Peptide Prevents Aberrant Ca2+ Leakage through the Ryanodine Receptor by Suppressing Mitochondrial Reactive Oxygen Species Production Induced by Isoproterenol in Failing Cardiomyocytes. (2016)
  • Author(s): Murakami W, Kobayashi S, Susa T, Nanno T, Ishiguchi H, Myoren T, Nishimura S, Kato T, Hino A, Oda T, Okuda S, Yamamoto T, Yano M.
  • Journal Title: PLoS One Volume: 11 Issue: 9 Pages: e0163250-e0163250
  • DOI: 10.1371/journal.pone.0163250
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker of inflammatory activity in patients with cardiac sarcoidosis (2015)
  • Author(s): Kobayashi S, Myoren T, Oda S, Inari M, Ishiguchi H, Murakami W, Fukuda M, Tanaka T, Okuda S, Nao T, Doi M, Yamada J, Okamura T, Hoshii Y, Suga K, Matsuzaki M, Yano M.
  • Journal Title: Int J Cardiol. Volume: 190 Pages: 319-328
  • DOI: 10.1016/j.ijcard.2015.04.144
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A low-dose β1-blocker in combination with milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum. (2015)
  • Author(s): Kobayashi S, Susa T, Ishiguchi H, Myoren T, Murakami W, Kato T, Fukuda M, Hino A, Suetomi T, Ono M, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Okuda S, Doi M, Yamamoto T, Yano M
  • Journal Title: PLoS One Volume: 10 Issue: 1 Pages: e0114314-e0114314
  • DOI: 10.1371/journal.pone.0114314
  • Peer Reviewed / Open Access
• [Presentation] Ryanodine receptor Targeting Therapy Restores Abnormal Intracellular Ca2+ Handling in the Compensated Pressure-Overloaded Heart (2017)
  • Author(s): Shigeki Kobayashi, Masafumi Yano
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 石川県、金沢市 （ホテル金沢）
  • Year and Date: 2017-03-19
  • Invited
• [Presentation] Dantrolene Prevents Right Ventricular Hypertrophy Without Reducing Pulmonary Arterial Pressure In Monocrotaline-induced PAH In Mice (2017)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Michiaki kono, Yoriomi Hamada, Go Fukui, Yoko Sufu, Takuma Nanno, Hironori Ishiguchi, Shigehiko Nishimura, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
  • Int'l Joint Research
• [Presentation] ダントロレンによるリアノジン受容体を分子標的とした心不全・不整脈治療の臨床応用 (2016)
  • Author(s): Shigeki Kobayashi
  • Organizer: 第37回日本臨床薬理学会学術総会
  • Place of Presentation: 鳥取県、米子市 （米子コンベンションセンター）
  • Year and Date: 2016-12-01
  • Invited
• [Presentation] Correction of the Defective Channel Gating of Cardiac Ryanodine Receptor Improves Cardiac Function and Suppresses Ventricular Arrhythmia in Post Myocardial Infarction Heart Failure (2016)
  • Author(s): Hironori Ishiguchi, Shigeki Kobayashi, Michiaki Kohno, Takuma Nanno, Gou Fukui, Yoko Sufu-Shimizu, Yoriomi Hamada, Takako Maeda, Shigehiko Nishimura, Tetsuro Oda, Shinnichi Okuda, Takeshi Ueyama, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 89th Scientific Session of American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Myocardial Oxidative Stress, Urinary 8-hydroxy-2’-deoxyguanosine, is Associated With Sustained Ventricular Tachycardia in Patient With Active Cardiac Sarcoidosis (2016)
  • Author(s): Hironori Ishiguchi, Shigeki Kobayashi, Michiaki Kohno, Takuma Nanno, Takeki Myoren, Seiko Oda, Hiroki Tateishi, Mamoru Mochizuki, Tetsuro Oda, Jutaro Yamada, Takayuki Okamura, Masafumi Yano
  • Organizer: 89th Scientific Session of American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] A Marked Increase in Myocardial Oxidative Stress Associated With Sympathetic Hyperactivity is Related to Transient Myocardial Dysfunction in Patients With Takotsubo Cardiomyopathy (2015)
  • Author(s): Takuma Nanno，Shigeki Kobayashi，Seiko Oda，Hironori Ishiguchi，Takeki Myoren，Yosuke Miyazaki，Takeshi Suetomi，Makoto Ono，Mamoru Mochizuki，Tetsuro Oda，Shinichi Okuda，Jutaro Yamada，Takayuki Okamura，Masafumi Yano
  • Organizer: 88th Scientific Session of American Heart Association
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Dantrolene Enhances Binding of Calmodulin to RyR2 in CPVT Which Mutation Located at Central Domain but Does Not Enhance That in CPVT With Mutation at CaM-like Domain (2015)
  • Author(s): Shigehiko Nishimura，Takeshi Yamamoto，Go Fukui，Takako Maeda，Akihiro Hino，Takeshi Suetomi，Makoto Ono，Mamoru Mochizuki，Tetsuro Oda，Shinichi Okuda，Shigeki Kobayashi，Masafumi Yano
  • Organizer: 88th Scientific Session of American Heart Association
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Dantrolene Cannot Inhibit Aberrant Ca2+ Release and Arrhythmias Without Calmodulin in Pressure Overload Heart Failure (2015)
  • Author(s): Go Fukui，Takeshi Yamamoto，Tkayoshi Kato，Takako Maeda，Shigehiko Nishimura，Akihiro Hino，Takeshi Suetomi，Makoto Ono，Mamoru Mochizuki，Tetsuro Oda，Shinichi Okuda，Shigeki Kobayashi，Masafumi Yano
  • Organizer: 88th Scientific Session of American Heart Association
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Book] 循環器内科「たこつぼ心筋症」 (2017)
  • Author(s): 小林 茂樹 他
  • Total Pages: 108
  • Publisher: 科学評論社
• [Book] 循環器内科｢心拍数と心機能｣ (2015)
  • Author(s): 小林茂樹、矢野雅文
  • Total Pages: 117
  • Publisher: 科学論評社
• [Book] 循環器内科｢β受容体制御による心不全治療｣ (2015)
  • Author(s): 小林茂樹、矢野雅文
  • Total Pages: 116
  • Publisher: 科学論評社
• [Book] 「静注用β１遮断薬ランジオロールを不整脈患者においてどう使うか」不整脈治療 update 第4巻 (2015)
  • Author(s): 小林茂樹
  • Total Pages: 224
  • Publisher: 医薬ジャーナル