Treatment of heart failure, cardiac hypertrophy, and fatal arrhythmia by ryanodine receptor-bound calmodulin regulation

• Project/Area Number: 20H03677
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamaguchi University
• Principal Investigator: YANO MASAFUMI 山口大学, 大学院医学系研究科, 教授 (90294628)
• Co-Investigator(Kenkyū-buntansha): 小田 哲郎 山口大学, 医学部附属病院, 講師 (40569290) ; 山本 健 山口大学, 大学院医学系研究科, 教授 (50363122) ; 小林 茂樹 山口大学, 医学部, 教授(連携講座) (90397993)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2022: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2020: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 心不全 / 致死的不整脈 / リアノジン受容体 / カルモジュリン / ダントロレン

Outline of Research at the Start

本研究では、RyR2へのCaMの結合親和性の増強が、拡張期Ca2+濃度上昇の抑制を介して心不全・心肥大・致死的不整脈に対する新たな包括的治療戦略となりうるかを実験的に証明するとともに、臨床的にも(RyR2安定化→CaM解離抑制作用を有する)ダントロレンの心不全・重症不整脈に対する有効性を多施設共同二重盲検ランダム化比較試験（RCT）により明らかにする。

Outline of Final Research Achievements

We have found that the cardiac Ca2+ release channel (ryanodine receptor: RyR2) present in the sarcoplasmic reticulum (SR) of cardiomyocytes is dysfunctional, especially the RyR2-calmodulin (CaM)-linked disorder is associated with heart failure, cardiac hypertrophy, and fatal arrhythmias. reported that it is deeply involved in the onset of We will prove that enhancing the binding affinity of CaM to RyR2 can be a new comprehensive therapeutic strategy for heart failure, cardiac hypertrophy, and fatal arrhythmias through suppression of diastolic Ca2+ concentration elevation, and clinically (RyR2 To clarify the efficacy of dantrolene for heart failure and severe arrhythmia by conducting a multicenter, double-blind, randomized controlled trial (RCT).

Academic Significance and Societal Importance of the Research Achievements

「心不全・致死的不整脈の要因としてCa2+ 漏出が重要である」との考え方は多くの研究施設間でコンセンサスが得られているが、いかなるRyR2内の分子連関によりCa2+ 漏出を生じるか？は明らかではない。その点、「点突然変異・酸化ストレス・（PKAまたはCaMKIIによる）過リン酸化が、共通してドメイン連関障害からCaM解離→Ca2+ 漏出を引き起こし心不全・心肥大・重症不整脈の発症に深く寄与しており、CaM解離を抑制することが心不全・心肥大・重症不整脈の治療に有効である」との考え方は斬新かつ独創的であり、数多くの論文dataによりその正当性は裏付けられている。

Research Products

• [Journal Article] RyR2-targeting therapy prevents left ventricular remodeling and ventricular tachycardia in post-infarction heart failure (2023)
  • Author(s): Fujii Shohei、Kobayashi Shigeki、Chang Yaowei、Nawata Junya、Yoshitomi Ryosuke、Tanaka Shinji、Kohno Michiaki、Nakamura Yoshihide、Ishiguchi Hironori、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Okuda Shinichi、Okamura Takayuki、Yamamoto Takeshi、Yano Masafumi
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 178 Pages: 36-50
  • DOI: 10.1016/j.yjmcc.2023.03.007
  • Peer Reviewed / Open Access
• [Journal Article] Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats (2023)
  • Author(s): Nawata Junya、Yamamoto Takeshi、Tanaka Shinji、Yano Yasutake、Uchida Tomoyuki、Fujii Shohei、Nakamura Yoshihide、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 34 Pages: 101449-101449
  • DOI: 10.1016/j.bbrep.2023.101449
  • Peer Reviewed / Open Access
• [Journal Article] Herpud1 modulates hypertrophic signals independently of calmodulin nuclear translocation in rat myocardium-derived H9C2 cells (2023)
  • Author(s): Fujioka Riko、Yamamoto Takeshi、Maruta Akihiro、Nakamura Yoshihide、Tominaga Naoomi、Inamitsu Masako、Oda Tetsuro、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 652 Pages: 61-67
  • DOI: 10.1016/j.bbrc.2023.02.038
  • Peer Reviewed / Open Access
• [Journal Article] Stabilizing cardiac ryanodine receptor with dantrolene treatment prevents left ventricular remodeling in pressure-overloaded heart failure mice (2023)
  • Author(s): Yano Yasutake、Kobayashi Shigeki、Uchida Tomoyuki、Chang Yaowei、Nawata Junya、Fujii Shohei、Nakamura Yoshihide、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Yamamoto Takeshi、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 642 Pages: 175-184
  • DOI: 10.1016/j.bbrc.2022.12.063
  • Peer Reviewed / Open Access
• [Journal Article] Stabilizing Tetrameric Structure of Ryanodine Receptor Cures Lethal Arrhythmia in Heart Failure (2022)
  • Author(s): Kobayashi Shigeki、Yamamoto Takeshi、Yoshiga Yasuhiro、Okamura Takayuki、Kawano Reo、Yano Masafumi
  • Journal Title: Circulation: Arrhythmia and Electrophysiology Volume: 15 Issue: 10 Pages: 714-717
  • DOI: 10.1161/circep.122.011220
  • Peer Reviewed / Open Access
• [Journal Article] Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells (2022)
  • Author(s): Uchida Tomoyuki、Oda Tetsuro、Yamamoto Takeshi、Inamitsu Masako、Sakai Chihiro、Uchinoumi Hitoshi、Suetomi Takeshi、Nakamura Yoshihide、Okamoto Yoko、Tateda Satomi、Fujii Shohei、Tanaka Shinji、Nawata Junya、Okamura Takayuki、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 628 Pages: 155-162
  • DOI: 10.1016/j.bbrc.2022.08.069
  • Peer Reviewed / Open Access
• [Journal Article] Dantrolene, a stabilizer of the ryanodine receptor, prevents collagen-induced arthritis. (2022)
  • Author(s): 58)Nawata T, Sakai H, Honda T, Otsuka M, Fujita H, Uchinoumi H, Kobayashi S, Yamamoto T, Asagiri M, Yano M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 624 Pages: 141-145
  • DOI: 10.1016/j.bbrc.2022.07.111
  • Peer Reviewed / Open Access
• [Journal Article] Herpud1 suppress angiotensin II induced hypertrophy in cardiomyocytes. (2022)
  • Author(s): Mikawa M, Sakai C, Yamamoto T, Nakamura Y, Tanaka S, Tominaga N, Inamitsu M, Oda T, Kobayashi S, Yano M.
  • Journal Title: Biochem Biophys Rep. Volume: 30 Pages: 101248-101248
  • DOI: 10.1016/j.bbrep.2022.101248
  • Peer Reviewed / Open Access
• [Journal Article] Stabilization of RyR2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension. (2022)
  • Author(s): Tanaka S, Yamamoto T, Mikawa M, Nawata J, Fujii S, Nakamura Y, Kato T, Fukuda M, Suetomi T, Uchinoumi H, Oda T, Okuda S, Okamura T, Kobayashi S, Yano M.
  • Journal Title: Heart Rhythm. Volume: S1547 Issue: 6 Pages: 00119-00119
  • DOI: 10.1016/j.hrthm.2022.02.003
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced oxidative stress and presence of ventricular aneurysm for risk prediction in cardiac sarcoidosis. (2022)
  • Author(s): Yoshitomi R, Kobayashi S, Yano Y, Nakashima Y, Fujii S, Nanno T, Ishiguchi H, Fukuda M, Yoshiga Y, Okamura T, Suga K, Kawano R, Yano M.
  • Journal Title: Heart Volume: 108 Issue: 6 Pages: 429-437
  • DOI: 10.1136/heartjnl-2021-320244
  • Peer Reviewed / Open Access
• [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] 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] 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
• [Presentation] Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II (CaMKII) signaling is essential for adverse cardiac remodeling (2021)
  • Author(s): Takeshi Suetomi，Shinichi Okuda，Satomi Tateda，Yoko Okamoto，Hitoshi Uchinoumi，Tetsuro Oda，Shigeki Kobayashi，Takeshi Yamamoto，Masafumi Yano
  • Organizer: 第38回国際心臓研究学会日本部会総会
• [Presentation] Enhancing calmodulin binding affinity to ryanodine receptor type2 can be a therapeutic target for heart failure with preserved ejection fraction (2021)
  • Author(s): Tomoyuki Uchida，Tetsuro Oda，Takeshi Suetomi，Takeshi Yamamoto，Shigeki Kobayashi，Yoshihide Nakamura，Shohei Fujii，Hitoshi Uchinoumi，Shinji Tanaka，Jyunya Nawata，Masafumi Yano
  • Organizer: 第38回国際心臓研究学会日本部会総会
• [Presentation] RyR2-targeting therapy improves left ventricular remodeling after myocardial infarction (2021)
  • Author(s): Shohei Fujii，Shigeki Kobayashi，Yaowei Chang，Jyunya Nawata，Shinji Tanaka，Yoshihide Nakamura，Takeshi Suetomi，Hitoshi Uchinoumi，Tetsuro Oda，Takeshi Yamamoto，Masafumi Yano
  • Organizer: 第38回国際心臓研究学会日本部会総会
• [Presentation] Stabilization of RyR2 maintains right ventricular function, and improves prognosis in pulmonary hypertension (2021)
  • Author(s): Shinji Tanaka，Takeshi Yamamoto，Jyunya Nawata，Shohei Fujii，Yoshihide Nakamura，Hitoshi Uchinoumi，Tetsuro Oda，Shigeki Kobayashi，Masafumi Yano
  • Organizer: 第38回国際心臓研究学会日本部会総会
• [Presentation] Improving Ca2+ handling prevent doxorubicin induced cardiomyopathy in mice (2021)
  • Author(s): Yoshihide Nakamura，Takeshi Yamamoto， Shinji Tanaka，Hitoshi Uchinoumi，Tetsuro Oda，Masafumi Yano
  • Organizer: 第38回国際心臓研究学会日本部会総会