An attempt to regress cardiac hypertrophy by cardiomyocyte intracellular calmodulin control

• Project/Area Number: 16K15443
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• 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): 山本 健 山口大学, 大学院医学系研究科, 教授 (50363122)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: リアノジン受容体 / カルモジュリン / 心肥大 / EC coupling / 心不全 / 不整脈

Outline of Final Research Achievements

We found a mutation that strengthened the binding of CaM to RyR2 and created a knock-in (KI) mouse (CaM HA mouse) incorporating the mutant RyR2. Suppression of dissociation of CaM from RyR2 in dantrolene administered WT mice and CaMHA mice suppressed the Ca leak from RyR2 as well as that the hypertrophy of cardiomyocytes after TAC was significantly suppressed.

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] 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] 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] Urinary 8-Hydroxy-2′-Deoxyguanosine as a Myocardial Oxidative Stress Marker Is Associated With Ventricular Tachycardia in Patients With Active Cardiac Sarcoidosis (2017)
  • Author(s): Ishiguchi H, Kobayashi S, Myoren T, Kohno M, Nanno T, Murakami W, Oda S, Oishi K, Okuda S, Okada M, Suga K, Yano M.
  • Journal Title: Cardiovascular Imaging, Volume: 10 Issue: 12
  • DOI: 10.1161/circimaging.117.006764
  • Peer Reviewed
• [Journal Article] Serial changes in the side-branch ostial area after main-vessel stenting with kissing balloon inflation for coronary bifurcation lesions, assessed by 3D optical coherence tomography. (2017)
  • Author(s): Fujimura T, Okamura T, Tateishi H, Nakamura T, Yamada J, Oda T, Mochizuki M, Nishimura S, Nishimura T, Yano M.
  • Journal Title: Eur Heart J Cardiovasc Imaging Volume: - Issue: 10 Pages: 1-9
  • DOI: 10.1093/ehjci/jex213
  • Peer Reviewed
• [Journal Article] Macroreentrant form of an adenosine 5′-triphosphate sensitive atrial tachycardia arising from the vicinity of the atrioventricular node involving the tricuspid and mitral annuli as its reentrant circuit (2017)
  • Author(s): Ueyama Takeshi、Shimizu Akihiko、Yoshiga Yasuhiro、Ono Makoto、Fumimoto Tomoko、Yano Masafumi
  • Journal Title: HeartRhythm Case Reports Volume: 3 Issue: 6 Pages: 289-293
  • DOI: 10.1016/j.hrcr.2017.03.001
  • Peer Reviewed
• [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
• [Presentation] Stabilization of CaMKII-phosphorylated RyR2Prevents the Development of Age-related Car-diomyopathy Caused by Transgenic CaMKIIδc Overexpression (2018)
  • Author(s): Yoko Sufu, Shinichi Okuda, Yoko Okamoto, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Dantrolene Prevents Right Ventricular Hypertro-phy without Reducing Pulmonary Arterial Pres-sure in Monocrotaline-Induced PAH in Mice (2018)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Go Fukui, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Ryanodine Receptor Targeting Therapy InhibitsCardiomyocyte Hypertrophy and RelaxationImpairment in the Compensated Pressure-Overloaded Heart (2018)
  • Author(s): Michiaki Kono, Shigeki Kobayashi, Toshiro Kajii, Takuma Nanno, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Stabilization of Camkii-Phosphorylated Ryr2 by Dantrolene Prevents the Development of Age-Related Cardiomyopathy Caused by CamkiiδC Overexpression (2017)
  • Author(s): Yoko S Shimizu, Shinichi Okuda, Yoko Okamoto, Shigehiko Nishimura, Takayoshi Kato, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto and Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Channel Pore Mutation of RyR2 Cause Calcium Leak Independent of FKBP12.6-RyR2 and Calmodulin-RyR2 Affinity in R4496C/+ Knock-in Mouse (2017)
  • Author(s): Hitoshi Uchinoumi, Ivanita Stefanon, Yi Yang, Mena Said, Xiaoqiong Dong, Rogerio Faustino, Jose L Puglisi, Ye Chen-Izu, Razvan L Cornea, Xander H Wehrens, Wayne S Chen, Takeshi Yamamoto, Yano Masafumi and Donald M Bers
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Effect of Site Dependent RyR Stabilizers; a Clue to Trace a Signal Transmission Pathway Inside the RyR Molecule (2017)
  • Author(s): Go Fukui, Takeshi Yamamoto, Michiaki Kono, Yoshihide Nakamura, Takuma Nanno, Yoriomi Hamada, Yoko Sufu, Hironori Ishiguchi, Shigehiko Nishimura, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi and Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
• [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
• [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): 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