Novel treatment of arrhythmia and heart failure by controlling the domain of ryanodine receptors

• Project/Area Number: 18K08108
• 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: Yamamoto Takeshi 山口大学, 大学院医学系研究科, 教授 (50363122)
• Co-Investigator(Kenkyū-buntansha): 小田 哲郎 山口大学, 医学部附属病院, 助教 (40569290) ; 小林 茂樹 山口大学, 大学院医学系研究科, 准教授 (90397993)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: リアノジン受容体 / カルモジュリン / 心肥大 / 不整脈 / 心不全 / 致死的不整脈

Outline of Final Research Achievements

The principal investigator discovered an amino acid mutation that significantly enhances the binding affinity of CaM for RyR2, and succeeded in creating a knock-in (KI) mouse: (RyR2 V3599K KI mouse) incorporating this mutation. By mating these mice with R2474S CPVT type mice, CaM dissociation during catecholamine stimulation was suppressed, and the motor-induced ventricular tachycardia that occurs in CPVT mice completely disappeared. In this RyR2 V3599K KI mouse, cardiac enlargement and cardiac hypertrophy due to TAC were almost completely suppressed. Furthermore, in WT mice, CaM was dissociated from RyR2 after 2 weeks of TAC, whereas it was suppressed in KI mice.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、新しい心不全、心肥大の治療法をもたらす。左心不全のみならず、肺高血圧に伴う右心不全にも応用できると考える。また、SRからのCa2+ leak抑制のみならず、心筋以外の組織ではERからのCa2+ leak抑制によりER stressを抑制できるため、アルツハイマー病、糖尿病、脂肪肝炎など様々な疾患への応用が可能となる可能性がある。

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] Cytokine Adsorption to Polymyxin B-Immobilized Fiber: An in vitro Study (2020)
  • Author(s): Utsunomiya Toshiaki、Mimura-Kimura Yuka、Yamamoto Takeshi、Aoe Keisuke、Oishi Keiji、Kamei Haruhito、Matsunaga Kazuto、Yano Masafumi、Mimura Yusuke
  • Journal Title: Blood Purification Volume: 50 Issue: 2 Pages: 1-8
  • DOI: 10.1159/000510290
  • Peer Reviewed / 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] 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] Factors limiting habitual exercise in patients with chronic heart failure: a multicenter prospective cohort study. (2020)
  • Author(s): Tadaki S, Sakata Y, Miura Y, Nochioka K, Miura M, Miyata S, Asakura M, Shimada K, Yamamoto T, Fukumoto Y, Kadokami T, Yasuda S, Miura T, Ando SI, Yano M, Kitakaze M, Daida H, Shimokawa H.
  • Journal Title: Heart Vessels Volume: 35 Issue: 5 Pages: 655-664
  • DOI: 10.1007/s00380-019-01529-4
  • Peer Reviewed / Open Access
• [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
• [Presentation] Stabilization of CaMKII-phosphorylated RyR2 By Dantrolene Prevents the Development of Age-related Cardiomyopathy in CaMKIIδc Transgenic Mice (2019)
  • Author(s): Yoko Sufu-Shimizu, Shinichi Okuda, Yoko Okamoto, Takayoshi Kato, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: AHA Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] The Difference of Calmodulin-Ryanodine Receptor Affinity Between N-terminal, Central and C-terminal RyR2-CPVT Knock-in Mice (2019)
  • Author(s): Hitoshi Uchinoumi, Xiaoqiong Dong, Ivanita Stefanon, Mena Said, Rogerio Faustino, Razvan L Cornea, Univ of Minnesota, Xander H.t. Wehrens, Takeshi Yamamoto, Masafumi Yano, Donald M Bers
  • Organizer: AHA Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] Critical Role of Ryanodine Receptor Bound Calmodulin to Prevent Catecholaminergic Polymorphic Ventricular Tachycardia (2019)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Shigeki Kobayashi, Masaki Tamitani, Yoriomi Hamada, Go Fukui, Xiaojuan Xu, Shigehiko Nishimura, Takayoshi Kato, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Masafumi Yano
  • Organizer: AHA BCVS 2019
  • Int'l Joint Research