Comprehensive strategy of heart failure, cardiac hypertrophy and lethal arrhythmia via stabilizing the stricture of ryanodine receptor

• Project/Area Number: 26293189
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YANO Masafumi 山口大学, 医学(系)研究科(研究院), 教授 (90294628)
• 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, 医学部附属病院, 講師 (90397993)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: リアノジン受容体 / Caハンドリング / カルモジュリン / 筋小胞体 / 致死的不整脈 / Ca2+ハンドリング / CPVT / リアニジン受容体

Outline of Final Research Achievements

In this study, we succeeded in stabilizing the structure of RyR by controlling the affinity of RyR-bound CaM, and further stabilizing the structure of RyR improves Ca handling of the defective myocardium, effective treatment of heart failure It turned out to be a law. We also clarified that stabilization of RyR structure can also suppress cardiac hypertrophy by preventing divergence of CaM from RyR. Finally, it was clarified that it is possible to treat genetic lethal arrhythmia and fatal arrhythmia in experimental heart failure model by structural stabilization of RyR.

Research Products

• [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] 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] 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] Oxidation of ryanodine receptor (RyR) and calmodulin enhance Ca release and pathologically alter, RyR structure and calmodulin affinity. (2015)
  • Author(s): Oda T, Yang Y, Uchinoumi H, Thomas DD, Chen-Izu Y, Kato T, Yamamoto T, Yano M, Cornea RL, Bers DM.
  • Journal Title: J Mol Cell Cardiol Volume: 85 Pages: 240-248
  • DOI: 10.1016/j.yjmcc.2015.06.009
  • Peer Reviewed
• [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
• [Journal Article] Comparison of neointimal coverage and extra-stent lumen between sirolimus and everolimus-eluting stent using optical coherence tomography. (2015)
  • Author(s): Oda T, Okamura T, Yamada J, Miyagi N, Uehara H, Nao T, Tateishi H, Maeda T, Nakamura T, Shiraishi K, Nakashima T, Nishimura S, Miura T, Matsuzaki M, Yano M
  • Journal Title: Heart Vessels Volume: 印刷中 Issue: 4 Pages: 449-456
  • DOI: 10.1007/s00380-015-0630-z
  • Peer Reviewed / Open Access
• [Journal Article] New quantitative method to diagnose coronary in-stent restenosis by 64-multislice computed tomography (2015)
  • Author(s): Yoshimura M, Nao T, Miura T, Okada M, Nakashima Y, Fujimura T, Okamura T, Yamada J, Matsunaga N, Matsuzaki M, Yano M.
  • Journal Title: J Cardiol Volume: 65 Issue: 1 Pages: 57-62
  • DOI: 10.1016/j.jjcc.2014.03.013
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes (2014)
  • Author(s): Fukuda M, Yamamoto T, Nishimura S, Kato T, Murakami W, Hino A, Ono M, Tateishi H, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M
  • Journal Title: Biochem Biophys Res Commun Volume: 448(1) Issue: 1 Pages: 1-7
  • DOI: 10.1016/j.bbrc.2014.03.152
  • Peer Reviewed / Open Access
• [Presentation] Nuclear Translocation of Calmodulin, Which Dissociated From Cardiac Ryanodine Receptor, Promotes the Pathological Cardiac Hypertrophy (2016)
  • Author(s): Tetsuro Oda, Takeshi Yamamoto, Takayoshi Kato, Shigehiko Nishimura, Go Fukui, Shinichi Okuda, Shigeki Kobayashi, Donald Bers and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Improvement of Defective Channel Function on RyR2 Mediated by CaMKII Activation Suppresses Arrhythmogenesis in TnT-related Hypertrophic Cardiomyopathy (2016)
  • Author(s): Shinichi Okuda, Yoko Sufu-Shimizu, Takayoshi Kato, Yoko Okamoto, Shigehiko Nishimura, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [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 and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Correction of Impaired Calmodulin Binding to Ryr2 as a Novel Therapy of Lethal Arrhythmia in the Pressure-Overloaded Heart Failure (2016)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Takayoshi Kato, Yoriomi Hamada, Go Fukui, Yoko Sufu, Takuma Nanno, Shigehiko Nishimura, Hironori Ishiguchi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • 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: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, FL (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] High Affinity CaM, but Not Normal Affinity CaM Can Prevent Arrhythmias in CPVT Which Mutation Is Located at CaM-like Domain of RyR2 (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: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, FL (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, Takayoshi Kato, Takako Maeda, Shigehiko Nishimura, Akihiro Hino, Takeshi Suetomi, Makoto Ono, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, FL (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research