心筋細胞内カルシウム制御による心不全・心肥大・致死的不整脈の包括的治療法の確立

2013 年度 研究成果報告書

• 研究課題/領域番号: 23390215
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 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, 医学(系)研究科(研究院), 教授 (90294628)
• 研究分担者: 小林 茂樹 山口大学, 医学部附属病院, 講師 (90397993)
• 研究期間 (年度): 2011-04-01 – 2014-03-31
• キーワード: 心不全 / 筋小胞体 / カルシウム / リアノジン受容体

研究概要

3年間でCPVT、圧負荷心肥大などにおける不整脈発生の根本がRyR2からのCaリークであり、そのリークを起こすメカニズムとしてRyR2内のチャネル制御ドメインのunzipping、そしてその下流にあるcalmodulin結合ドメインの２つが重要な役割を果たしていることがわかった。さらにチャネル制御ドメインをzipさせるdantroleneや高親和性calmodulinなどの治療法も開発した。

研究成果

• [雑誌論文] Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes (2014)
  • 著者名/発表者名: 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
  • 雑誌名: Biochem Biophys Res Commun 巻: 448(1) ページ: 1-7
  • DOI: 10.1016/j.bbrc.2014.03.152
  • 査読あり
• [雑誌論文] A low-dose β 1-blocker effectively and safely slows the heart rate in patients with acute decompensated heart failure and rapid atrial fibrillation (2014)
  • 著者名/発表者名: Kobayashi S, Murakami W, Myoren T, Tateishi H, Okuda S, Doi M, Nao T, Wada Y, Matsuzaki M, Yano M
  • 雑誌名: Cardiology 巻: 127(2) ページ: 105-13
  • DOI: 10.1159/000355312
  • 査読あり
• [雑誌論文] Serial three-dimensional optical coherence tomography assessment of strut coverage and intraluminal structures after drug-eluting stent implantation (2014)
  • 著者名/発表者名: Maeda T, Okamura T, Yamada J, Nao T, Tateishi H, Yoshimura M, Oda T, Shiraishi K, Nakashima T, Nakamura T, Miura T, Yano M
  • 雑誌名: Cardiovasc Interv Ther 巻: 29(1) ページ: 31-9
  • DOI: 10.1007/s12928-013-0209-5
  • 査読あり
• [雑誌論文] Sarcomere gene mutations are associated with increased cardiovascular events in left ventricular hypertrophy : results from multicenter registration in Japan (2013)
  • 著者名/発表者名: Fujita T, Fujino N, Anan R, Tei C, Kubo T, Doi Y, Kinugawa S, Tsutsui H, Kobayashi S, Yano M, Asakura M, Kitakaze M, Komuro I, Konno T, Hayashi K, Kawashiri MA, Ino H, Yamagishi M
  • 雑誌名: JACC Heart Fail 巻: 1(6) ページ: 459-66
  • DOI: 10.1016/j.jchf.2013.08.007
  • 査読あり
• [雑誌論文] Does a ripple of Ca(2+) leak develop into a rogue wave that can trigger pathological hypertrophy? (2012)
  • 著者名/発表者名: Yano M, Okuda S
  • 雑誌名: J Am Coll Cardiol 巻: 63(15) ページ: 1580-2
  • DOI: 10.1016/j.jacc.2013.10.064
  • 査読あり
• [雑誌論文] Enhanced binding of calmodulin to the ryanodine receptor corrects contractile dysfunction in failing hearts (2012)
  • 著者名/発表者名: Hino A, Yano M, Kato T, Fukuda M, Suetomi T, Ono M, Murakami W, Susa T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M
  • 雑誌名: Cardiovasc Res 巻: 96(3) ページ: 433-43
  • DOI: 10.1093/cvr/cvs271
  • 査読あり
• [雑誌論文] Low-dose β -blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure (2012)
  • 著者名/発表者名: Kobayashi S, Susa T, Tanaka T, Murakami W, Fukuta S, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Okamura T, Yano M, Matsuzaki M
  • 雑誌名: Circ J 巻: 76(7) ページ: 1646-53
  • 査読あり
• [雑誌論文] Urinary 8-hydroxy-2' -deoxyguanosine as a novel biomarker for predicting cardiac events and evaluating the effectiveness of carvedilol treatment in patients with chronic systolic heart failure (2012)
  • 著者名/発表者名: Susa T, Kobayashi S, Tanaka T, Murakami W, Akashi S, Kunitsugu I, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Ueyama T, Okamura T, Yano M, Matsuzaki M
  • 雑誌名: Circ J 巻: 76(1) ページ: 117-26
  • 査読あり
• [雑誌論文] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca²+ release leading to catecholaminergic polymorphic ventricular tachycardia (2011)
  • 著者名/発表者名: Suetomi T, Yano M, Uchinoumi H, Fukuda M, Hino A, Ono M, Xu X, Tateishi H, Okuda S, Doi M, Kobayashi S, Ikeda Y, Yamamoto T, Ikemoto N, Matsuzaki M
  • 雑誌名: Circulation 巻: 124(6) ページ: 682-94
  • DOI: 10.1161/CIRCULATIONAHA
  • 査読あり
• [雑誌論文] Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters (2011)
  • 著者名/発表者名: Yoshida M, Ohkusa T, Nakashima T, Takanari H, Yano M, Takemura G, Honjo H, Kodama I, Mizukami Y, Matsuzaki M
  • 雑誌名: Cardiovasc Res 巻: 92(1) ページ: 95-105
  • DOI: 10.1093/cvr/cvr182
  • 査読あり
• [学会発表] Dantrolene May Suppress Arrhythmogenesis by Inhibition of CaMKII-mediated Aberrant Ca2+ Release Within the Ryanodine Receptor in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy (2013)
  • 著者名/発表者名: Shinichi Okuda, Masakazu Fukuda, Takayoshi Katoh, Shigehiko Nishimura, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • 学会等名: 86th Scientific Session of American Heart Association
  • 発表場所: Dallas(U. S. A)
  • 年月日: 2013-11-16
• [学会発表] A Novel Selective EP4 Receptor Agonist Improves Intracellular Ca2+ Handling and Cardiomyocyte Function in Intact Failing Cardiomyocytes (2013)
  • 著者名/発表者名: Wakako Murakami, Shigeki Kobayashi, Takeki Myoren, Shigehiko Nishimura, Takayoshi Katoh, Masakazu Fukuda, Makoto Ono, Hiroki Tateishi, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • 学会等名: 86th Scientific Session of American Heart Association
  • 発表場所: Dallas(U. S. A)
  • 年月日: 2013-11-16
• [学会発表] Dantrolene Inhibits Aberrant Ca2+ Release and Arrhythmogenesis via Enhancing Binding of Calmodulin to RyR2 in CPVT-Associated Mutation (2013)
  • 著者名/発表者名: Masakazu Fukuda, Takeshi Yamamoto, Shigehiko Nishimura, Takeki Myouren, Takayoshi Katoh, Wakako Murakami, Makoto Ono, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • 学会等名: 86th Scientific Session of American Heart Association
  • 発表場所: Dallas(U. S. A)
  • 年月日: 2013-11-16
• [学会発表] Fixing Ca2+ Leakage From Cardiac Ryanodine Receptor by Low-dose of β Blocker Safely Enhances Inotropic Response to Milrinone in Acute Heart Failure (2012)
  • 著者名/発表者名: Shigeki Kobayashi, Wakako Murakami, Takayoshi Kato, Masakazu Fukuda, Akihiro Hino, Hiroki Tateishi, Takeshi Yamamoto, Takeshi Yamamoto, Masafumi Yano, Masunori Matsuzaki
  • 学会等名: 85th Scientific Session of American Heart Association
  • 発表場所: Los Angeles(U. S. A)
  • 年月日: 2012-11-03
• [学会発表] Urinary 8-hydroxy-2' -deoxyguanosine as a Novel Marker of Left Ventricular Remodelling in Patients With Dilated Cardiomyopathy (2012)
  • 著者名/発表者名: Wakako Murakami, Shigeki Kobayashi, Takamasa Oda, Hiroki Tateishi, Tomoko Nao, Jutaro Yamada, Takayuki Okamura, Masafumi Yano, Masunori Matsuzaki
  • 学会等名: 85th Scientific Session of American Heart Association
  • 発表場所: Los Angeles(U. S. A)
  • 年月日: 2012-11-03
• [学会発表] Elevated Myocardial Oxidative Stress Induced by Catecholamines Related to Transient Left Ventricular Cysfunction in Patients With Takotsubo Cardiomyopathy (2012)
  • 著者名/発表者名: Wakako Murakami, Shigeki Kobayashi, Tadamitsu Nakashima, Hiroki Tateishi, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Tomoko Nao, Jutaro Yamada, Takayuki Okamura, Masafumi Yano, Masunori Matsuzaki
  • 学会等名: 85th Scientific Session of American Heart Association
  • 発表場所: Los Angeles(U. S. A)
  • 年月日: 2012-11-03
• [学会発表] Urinary 8-hydroxy-2' -deoxyguanosine, An Oxidative Stress Marker, Predicts The Inflammatory Activity within the Heart in Patients with Cardiac Sarcoidosi (2012)
  • 著者名/発表者名: Shigeki Kobayashi, Wakako Murakami, Seiko Fukuta, Masakazu Fukuda, Shinichi Okuda, Tomoko Nao, Masahiro Doi, Yasuaki Wada, Masafumi Yano, Masunori Matsuzaki
  • 学会等名: 85th Scientific Session of American Heart Association
  • 発表場所: Los Angeles(U. S. A)
  • 年月日: 2012-11-03