心筋細胞内カルモジュリン制御による心肥大退縮の試み

• 研究課題/領域番号: 16K15443
• 研究種目: 挑戦的萌芽研究
• 配分区分: 基金
• 研究分野: 循環器内科学
• 研究機関: 山口大学
• 研究代表者: 矢野 雅文 山口大学, 大学院医学系研究科, 教授 (90294628)
• 研究分担者: 山本 健 山口大学, 大学院医学系研究科, 教授 (50363122)
• 研究期間 (年度): 2016-04-01 – 2018-03-31
• 研究課題ステータス: 完了 (2017年度)
• 配分額: 3,510千円 (直接経費: 2,700千円、間接経費: 810千円); 2017年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円); 2016年度: 1,950千円 (直接経費: 1,500千円、間接経費: 450千円)
• キーワード: 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

研究成果の概要

我々はRyR2に対するCaMの結合を強める変異を見いだし、その変異RyR2を組み込んだノックイン(KI)マウス(CaM HAマウス)を作成した。ダントロレン投与WTマウス、およびCaMHAマウスにおいては、RyR2からのCaMの解離が抑制された結果、RyR2からのCa leakが押さえられるばかりでなく、TAC後の心筋細胞の肥大が有意に抑制されることがわかった。

研究成果

• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: Heart Rhythm 巻: 印刷中 号: 6 ページ: 905-914
  • DOI: 10.1016/j.hrthm.2018.02.006
  • 査読あり / 国際共著
• [雑誌論文] 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)
  • 著者名/発表者名: Okuda Shinichi、Sufu-Shimizu Yoko、Kato Takayoshi、Fukuda Masakazu、Nishimura Shigehiko、Oda Tetsuro、Kobayashi Shigeki、Yamamoto Takeshi、Morimoto Sachio、Yano Masafumi
  • 雑誌名: Biochemical and Biophysical Research Communications 巻: 496 号: 4 ページ: 1250-1256
  • DOI: 10.1016/j.bbrc.2018.01.181
  • 査読あり / 国際共著
• [雑誌論文] Strict sequential catheter ablation strategy targeting the pulmonary veins and superior vena cava for persistent atrial fibrillation. (2018)
  • 著者名/発表者名: Yoshiga Y, Shimizu A, Ueyama T, Ono M, Fukuda M, Fumimoto T, Ishiguchi H, Omuro T, Kobayashi S, Yano M.
  • 雑誌名: J Cardiol 巻: in press 号: 2 ページ: 128-134
  • DOI: 10.1016/j.jjcc.2018.01.004
  • 査読あり
• [雑誌論文] Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure. (2017)
  • 著者名/発表者名: 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.
  • 雑誌名: Heart Rhythm 巻: 14 号: 1 ページ: 120-127
  • DOI: 10.1016/j.hrthm.2016.10.019
  • 査読あり / オープンアクセス / 国際共著 / 謝辞記載あり
• [雑誌論文] Urinary 8-Hydroxy-2′-Deoxyguanosine as a Myocardial Oxidative Stress Marker Is Associated With Ventricular Tachycardia in Patients With Active Cardiac Sarcoidosis (2017)
  • 著者名/発表者名: Ishiguchi H, Kobayashi S, Myoren T, Kohno M, Nanno T, Murakami W, Oda S, Oishi K, Okuda S, Okada M, Suga K, Yano M.
  • 雑誌名: Cardiovascular Imaging, 巻: 10 号: 12
  • DOI: 10.1161/circimaging.117.006764
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Fujimura T, Okamura T, Tateishi H, Nakamura T, Yamada J, Oda T, Mochizuki M, Nishimura S, Nishimura T, Yano M.
  • 雑誌名: Eur Heart J Cardiovasc Imaging 巻: - 号: 10 ページ: 1-9
  • DOI: 10.1093/ehjci/jex213
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Ueyama Takeshi、Shimizu Akihiko、Yoshiga Yasuhiro、Ono Makoto、Fumimoto Tomoko、Yano Masafumi
  • 雑誌名: HeartRhythm Case Reports 巻: 3 号: 6 ページ: 289-293
  • DOI: 10.1016/j.hrcr.2017.03.001
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: PLoS One 巻: 11 号: 9 ページ: e0163250-e0163250
  • DOI: 10.1371/journal.pone.0163250
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] An oxidative stress biomarker, urinary 8-hydroxy-2'-deoxyguanosine, predicts cardiovascular-related death after steroid therapy for patients with active cardiac sarcoidosis. (2016)
  • 著者名/発表者名: Myoren T, Kobayashi S, Oda S, Nanno T, Ishiguchi H, Murakami W, Okuda S, Okada M, Takemura G, Suga K, Matsuzaki M, Yano M.
  • 雑誌名: Int J Cardiol 巻: 17 ページ: 206-213
  • DOI: 10.1016/j.ijcard.2016.03.003
  • 査読あり / オープンアクセス / 国際共著
• [学会発表] Stabilization of CaMKII-phosphorylated RyR2Prevents the Development of Age-related Car-diomyopathy Caused by Transgenic CaMKIIδc Overexpression (2018)
  • 著者名/発表者名: Yoko Sufu, Shinichi Okuda, Yoko Okamoto, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • 学会等名: 第82回日本循環器学会学術集会
• [学会発表] Dantrolene Prevents Right Ventricular Hypertro-phy without Reducing Pulmonary Arterial Pres-sure in Monocrotaline-Induced PAH in Mice (2018)
  • 著者名/発表者名: Yoshihide Nakamura, Takeshi Yamamoto, Go Fukui, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • 学会等名: 第82回日本循環器学会学術集会
• [学会発表] Ryanodine Receptor Targeting Therapy InhibitsCardiomyocyte Hypertrophy and RelaxationImpairment in the Compensated Pressure-Overloaded Heart (2018)
  • 著者名/発表者名: Michiaki Kono, Shigeki Kobayashi, Toshiro Kajii, Takuma Nanno, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • 学会等名: 第82回日本循環器学会学術集会
• [学会発表] Stabilization of Camkii-Phosphorylated Ryr2 by Dantrolene Prevents the Development of Age-Related Cardiomyopathy Caused by CamkiiδC Overexpression (2017)
  • 著者名/発表者名: Yoko S Shimizu, Shinichi Okuda, Yoko Okamoto, Shigehiko Nishimura, Takayoshi Kato, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto and Masafumi Yano
  • 学会等名: 90th Scientific Session of American Heart Association
• [学会発表] Channel Pore Mutation of RyR2 Cause Calcium Leak Independent of FKBP12.6-RyR2 and Calmodulin-RyR2 Affinity in R4496C/+ Knock-in Mouse (2017)
  • 著者名/発表者名: 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
  • 学会等名: 90th Scientific Session of American Heart Association
• [学会発表] Effect of Site Dependent RyR Stabilizers; a Clue to Trace a Signal Transmission Pathway Inside the RyR Molecule (2017)
  • 著者名/発表者名: 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
  • 学会等名: 90th Scientific Session of American Heart Association
• [学会発表] Dantrolene Prevents Right Ventricular Hypertrophy Without Reducing Pulmonary Arterial Pressure In Monocrotaline-induced PAH In Mice (2017)
  • 著者名/発表者名: 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
  • 学会等名: 90th Scientific Session of American Heart Association
• [学会発表] Nuclear Translocation of Calmodulin, Which Dissociated From Cardiac Ryanodine Receptor, Promotes the Pathological Cardiac Hypertrophy (2016)
  • 著者名/発表者名: Tetsuro Oda, Takeshi Yamamoto, Takayoshi Kato, Shigehiko Nishimura, Go Fukui, Shinichi Okuda, Shigeki Kobayashi, Donald Bers and Masafumi Yano
  • 学会等名: American Heart Association Scientific Sessions 2016
  • 発表場所: New Orleans, USA
  • 年月日: 2016-11-12
  • 国際学会
• [学会発表] Improvement of Defective Channel Function on RyR2 Mediated by CaMKII Activation Suppresses Arrhythmogenesis in TnT-related Hypertrophic Cardiomyopathy (2016)
  • 著者名/発表者名: Okuda, Yoko Sufu-Shimizu, Takayoshi Kato, Yoko Okamoto, Shigehiko Nishimura, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto and Masafumi Yano
  • 学会等名: American Heart Association Scientific Sessions 2016
  • 発表場所: New Orleans, USA
  • 年月日: 2016-11-12
  • 国際学会
• [学会発表] Correction of the Defective Channel Gating of Cardiac Ryanodine Receptor Improves Cardiac Function and Suppresses Ventricular Arrhythmia in Post Myocardial Infarction Heart Failure (2016)
  • 著者名/発表者名: 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
  • 学会等名: American Heart Association Scientific Sessions 2016
  • 発表場所: New Orleans, USA
  • 年月日: 2016-11-12
  • 国際学会
• [学会発表] Correction of Impaired Calmodulin Binding to Ryr2 as a Novel Therapy of Lethal Arrhythmia in the Pressure-Overloaded Heart Failure (2016)
  • 著者名/発表者名: 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
  • 学会等名: American Heart Association Scientific Sessions 2016
  • 発表場所: New Orleans, USA
  • 年月日: 2016-11-12
  • 国際学会