細胞内カルシウム放出制御による新しい悪性高熱症・不整脈の治療開発

2010 年度 研究成果報告書

• 研究課題/領域番号: 20591805
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 麻酔・蘇生学
• 研究機関: 山口大学
• 研究代表者: 小林 茂樹 山口大学, 医学部附属病院, 助教 (90397993)
• 研究分担者: 山本 健 山口大学, 大学院・医学系研究科, 助教 (50363122) ; 矢野 雅文 山口大学, 医学部付属病院, 講師 (90294628)
• 研究期間 (年度): 2008 – 2010
• キーワード: 悪性高熱症 / 心室頻拍症 / 心不全 / ダントロレン / リアノジン受容体

研究概要

悪性高熱症の治療薬であるダントロレンは、1)イヌ心不全モデルや2)リアノジン受容体(RyR2)点突然変異(R2474S/+)ノックインマウスモデル(カテコラミン誘発性心室頻拍モデル)において、心筋型リアノジン受容体(RyR2)のドメイン連関障害を是正することにより、RyR2からのCa^<2+>漏出を抑制し、心機能の改善や心室頻拍の抑制を来すことを証明した。以上により、ダントロレンは、リアノジン受容体を分子標的とした新しい心不全・致死的不整脈の治療薬となることが示唆された。

研究成果

• [雑誌論文] Urinary8-hydroxy-2'-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure. (2011)
  • 著者名/発表者名: Kobayashi S, Susa T, Tanaka T, Wada Y, Okuda S, Doi M, Nao T, Yoshiga Y, Yamada J, Okamura T, Ueyama T, Kawamura S, Yano M, Matsuzaki M.
  • 雑誌名: Eur J Heart Fail. 13 ページ: 29-36
  • 査読あり
• [雑誌論文] Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2 (R2474S/+) knock-in mouse model. (2010)
  • 著者名/発表者名: Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Yamamoto T, Matsuzaki M.
  • 雑誌名: Cir J. 74 ページ: 2579-2584
  • 査読あり
• [雑誌論文] Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure. (2010)
  • 著者名/発表者名: Ono M, Yano M, Hino A, Suetomi T, Xu X, Susa T, Uchinoumi H, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M.
  • 雑誌名: Cardiovasc Res. 87 ページ: 609-617
  • 査読あり
• [雑誌論文] Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. (2010)
  • 著者名/発表者名: Xu X, Yano M, Uchinoumi H, Hino A, Suetomi T, Ono M, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ikemoto N, Matsuzaki M.
  • 雑誌名: Biochem Biophys Res Commun. 394 ページ: 660-666
  • 査読あり
• [雑誌論文] Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor. (2010)
  • 著者名/発表者名: Uchinoumi H, Yano M, Suetomi T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M.
  • 雑誌名: Cir Res. 81 ページ: 1413-1423
  • 査読あり
• [雑誌論文] Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing inter-domain interactions within the ryanodine receptor. (2009)
  • 著者名/発表者名: Kobayashi S, Yano M, Suetomi T, Ono M, Tateishi H, Mochizuki M, Xu X, Uchinoumi H, Okuda S, Yamamoto T, Koseki N, Kyushiki H, IkemotoN, Matsuzaki M.
  • 雑誌名: J Am Coll Cardiol. 53 ページ: 1993-2005
  • 査読あり
• [雑誌論文] Role of ryanodine receptor as a Ca(2+) regulatory center in normal and failing hearts. (2009)
  • 著者名/発表者名: Yano M, Yamamoto T, Kobayashi S, Matsuzaki M.
  • 雑誌名: J Cardiol. 53 ページ: 1-7
  • 査読あり
• [雑誌論文] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • 著者名/発表者名: Tateishi H, Yano M, Mochizuki M, Suetomi T, Ono M, Xu X, Uchinoumi H, Okuda S, Oda T, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M.
  • 雑誌名: Cardiovasc Res. 81 ページ: 536-545
  • 査読あり
• [雑誌論文] Defective Ca2+ cycling as a key pathogenic mechanism of heart failure. (2008)
  • 著者名/発表者名: Yano M, Yamamoto T, Kobayashi S, Ikeda Y, Matsuzaki M.
  • 雑誌名: Circ J. 72 ページ: 22-30
  • 査読あり
• [雑誌論文] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. (2008)
  • 著者名/発表者名: Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M.
  • 雑誌名: Circulation. 117 ページ: 762-772
  • 査読あり
• [学会発表] Novel Inter-domain Interaction Within RyR2 as a Common Therapeutic Target by Channel Stabilization in Heart Failure and in Heart Failure and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). (2010)
  • 著者名/発表者名: Masafumi Yano, Masakazu Fukuda, Akihiro Hino, Takeshi Suetomi, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Masunori Matsuzaki.
  • 学会等名: 83rd Scientific Session of American Heart Association.
  • 発表場所: Chicago, USA.
  • 年月日: 2010-11-15
• [学会発表] Masunori Matsuzaki Urinary 8-Hydroxy-2'-Deoxyguanosine is a Biomarker for Evaluating the Inflammatory Activity and the Effectiveness to Corticosteroids in Patients with Cardiac Sarcoidosis. (2010)
  • 著者名/発表者名: Takeo Tanaka, Shigeki Kobayashi, Takehisa Susa, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Jutaro Yamada, Takeshi Ueyama, Takayuki Okamura, Shuji Kawamura, Masafumi Yano
  • 学会等名: 83rd Scientific Session of American Heart Association.
  • 発表場所: Chicago, USA.
  • 年月日: 2010-11-15
• [学会発表] Increased Affinity of Calmodulin Binding to Cardiac Ryanodine Receptor Corrects the Defective Channel Gating in Failing Hearts. (2010)
  • 著者名/発表者名: Akihiro Hino, Masafumi Yano, Masakazu Fukuda, Takeshi Suetomi, Makoto Ono, Xiaojuan Xu, Hitoshi Uchinoumi, Takehisa Susa, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Masunori Matsuzaki.
  • 学会等名: 83rd Scientific Session of American Heart Association.
  • 発表場所: Chicago, USA.
  • 年月日: 2010-11-15
• [学会発表] Correction of Defective Calmodulin Binding to Cardiac Ryanodine Receptor Inhibits Aberrant Ca2+ Release in CPVT-associated Mutation. (2010)
  • 著者名/発表者名: Masakazu Fukuda, Masafumi Yano, Akihiro Hino, Takeshi Suetomi, Xiaojuan Xu, Makoto Ono, Hitoshi Uchinoumi, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Masunori Matsuzaki.
  • 学会等名: 83rd Scientific Session of American Heart Association.
  • 発表場所: Chicago, USA.
  • 年月日: 2010-11-15
• [学会発表] Mutation-linked Defective Domain Interaction within the Ryanodine Receptor Causes Ca2+ Leak Leading to Catecholaminergic Polymorphic Ventricular Tachycardia. (2010)
  • 著者名/発表者名: Takeshi Suetomi, Masafumi Yano, Masakazu Fukuda, Akihiro Hino, Makoto Ono, Xiaojuan Xu, Takehisa Susa, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Masunori Matsuzaki.
  • 学会等名: 83rd Scientific Session of American Heart Association.
  • 発表場所: Chicago, USA.
  • 年月日: 2010-11-15
• [学会発表] Risk Stratification of Chronic Heart Failure by the Combination of Urinary 8-Hydroxy-2'-Deoxyguanosine and Plasma Brain Natriuretic Peptide. (2010)
  • 著者名/発表者名: Takehisa Susa, Shigeki Kobayashi, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Jutaro Yamada, Takayuki Okamura, Takeshi Ueyama, Masafumi Yano, Masunori Matsuzaki.
  • 学会等名: The 14th Annual Scientific Meeting of the Japanese Heart Failure Society.
  • 発表場所: 東京 京王プラザホテル
  • 年月日: 2010-10-07
• [学会発表] Mechanism of Destabilized RyR2 Channel in Catecholaminergic Polymorphic Ventricular Tachycardia. (2010)
  • 著者名/発表者名: Takeshi Suetomi, Masafumi Yano, Makoto Ohno, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Masahiro Doi, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Masunori Matsuzaki.
  • 学会等名: The 14th Annual Scientific Meeting of the Japanese Heart Failure Society.
  • 発表場所: 東京 京王プラザホテル
  • 年月日: 2010-10-07
• [学会発表] Correction of the defective inter-domain interaction within ryanodine receptor prevents the development of heart failure. (2010)
  • 著者名/発表者名: Hitoshi Uchinoumi, Masafumi Yano, Akihiro Hino, Takeshi Suetomi, Xiaojuan Xu, Makoto Ohno, Shinichi Okuda, MasahiroDoi, Shigeki Kobayashi, Takeshi Yamamoto, Masunori Matsuzaki.
  • 学会等名: 20th World Congress of the International Society for Heart Research.
  • 発表場所: 京都,京都国際会議場
  • 年月日: 2010-05-13
• [学会発表] Urine 8-hydroxy-2'-deoxyguanosine is a Marker for Predicting Mortality and Morbidity as well as Evaluating the Effectiveness of Beta-blocker Therapy in Patients with Chronic Heart Failure. (2010)
  • 著者名/発表者名: Takehisa Susa, Shigeki Kobayashi, Takeo Tanaka, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Jutaro Yamada, Takeshi Ueyama, Shuji Kawamura, Masafumi Yano, Masunori Matsuzaki.
  • 学会等名: 59th Annual Scientific Session of the American College of Cardiology.
  • 発表場所: Atlanta, USA.
  • 年月日: 2010-03-15
• [学会発表] Decreased Affinity of Calmodulin to the Cardiac Ryanodine Receptor Plays a Crucial Role in the CPVT-type Channel Disorder. (2010)
  • 著者名/発表者名: Xiaojuan Xu, Masafumi Yano, Akihiro Hino, Takeshi Suetomi, Makoto Ohno, Hitoshi Uchinoumi, Tetsuro Oda, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Tomoko Ohkusa, Masunori Matsuzaki.
  • 学会等名: 74th Annual Scientific Meeting of the Japanese Circulation Society.
  • 発表場所: 京都,京都国際会議場
  • 年月日: 2010-03-05
• [学会発表] Correction of Defective Conformational Regulation of the Cardiac Ryanodine Receptor is a New Therapeutic Strategy against Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). (2010)
  • 著者名/発表者名: Hitoshi Uchinoumi, Masafumi Yano, Takeshi Suetomi, Makoto Ohno, Xiaojuan Xu, Hiroki Tateishi, Tetsuro Oda, Shinichi Okuda, Masahiro Doi, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Tomoko Ohkusa, Masunori Matsuzaki.
  • 学会等名: The 74th Annual Scientific Meeting of the Japanese Circulation Society.
  • 発表場所: 京都,京都国際会議場
  • 年月日: 2010-03-05
• [学会発表] Interruption of Novel Inter-domain Interaction within RyR2 as a Common Therapeutic Target for Channel Stabilization in Heart Failure and CPVT. (2010)
  • 著者名/発表者名: Takeshi Yamamoto, Masafumi Yano, Akihiro Hino, Takeshi Suetomi, Makoto Ohno, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Masahiro Doi, Shigeki Kobayashi, Masunori Matsuzaki.
  • 学会等名: The 74th Annual Scientific Meeting of the Japanese Circulation Society.
  • 発表場所: 京都,京都国際会議場
  • 年月日: 2010-03-05
• [学会発表] Urinary 8-Hydroxy-2'Deoxyguanosine as an Oxidative Stress Biomarker in Patients with Chronic Heart Failure. (2010)
  • 著者名/発表者名: Shigeki Kobayashi, Takehisa Susa, Takeo Tanaka, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Yasuhiro Yoshiga, Jutaro Yamada, Takeshi Ueyama, Shuji Kawamura, Masafumi Yano, Masunori Matsuzaki.
  • 学会等名: The 74th Annual Scientific Meeting of the Japanese Circulation Society.
  • 発表場所: 京都,京都国際会議場
  • 年月日: 2010-03-05
• [学会発表] Correction of defective inter-domain interaction within the cardiac ryanodine receptor as a new therapeutic strategy against catecholaminergic polymorphic ventricular tachycardia (CPVT). (2009)
  • 著者名/発表者名: Hitoshi Uchinoumi, Masafumi Yano, Takeshi Suetomi, Makoto Ohno, Xiaojuan Xu, Shigeki Kobayashi, Takeshi Yamamoto, Masunori Matsuzaki.
  • 発表場所: 札幌,ロイトン札幌
  • 年月日: 2009-12-04
• [学会発表] Low-dose of β Blocker Improves Cardiac Function in Patients With Acute Heart Failure Partly by Inhibiting Ca2+ Leak Through the Ryanodine Receptor. (2009)
  • 著者名/発表者名: Shigeki Kobayashi, Takeo Tanaka, Takehisa Susa, Makoto Ohno, Hitoshi Uchinoumi, Shinichi Okuda, Masahiro Doi, Shuji Kawamura, Takeshi Yamamoto, Masafumi Yano, Masunori Matsuzaki.
  • 学会等名: 82nd Scientific Session of American Heart Association.
  • 発表場所: Orlando, USA.
  • 年月日: 2009-11-16
• [学会発表] Decreased Affinity of Calmodulin to RyR2 May Be a Sauce Mechanism of Leaky Channel in CPVT-associated Mutation. (2009)
  • 著者名/発表者名: Xiaojuan Xu, Masafumi Yano, Akihiro Hino, Takeshi Suetomi, Makoto Ohno, Hitoshi Uchinoumi, Tetsuro Oda, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Yasuhiro Ikeda, Takeshi Yamamoto, Tomoko Ohkusa, Masunori Matsuzaki.
  • 学会等名: 82nd Scientific Session of American Heart Association.
  • 発表場所: Orlando, USA.
  • 年月日: 2009-11-16
• [学会発表] Mutation-linked Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is Caused by Abnormally Tight Domain-Domain Interaction in RyR2. (2009)
  • 著者名/発表者名: Takeshi Suetomi, Masafumi Yano, Akihiro Hino, Makoto Ohno, Xiaojuan Xu, Takehisa Susa, Hitoshi Uchinoumi, Tetsuro Oda, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Yasuhiro Ikeda, Takeshi Yamamoto, Masunori Matsuzaki.
  • 学会等名: 82nd Scientific Session of American Heart Association.
  • 発表場所: Orlando, USA.
  • 年月日: 2009-11-16
• [学会発表] Correction of Defective Inter-domain Interaction Within the Cardiac Ryanodine Receptor as a New Therapeutic Strategy Against Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). (2009)
  • 著者名/発表者名: Hitoshi Uchinoumi, Masafumi Yano, Akihiro Hino, Takeshi Suetomi, Makoto Ohno, Xiaojuan Xu, Tetsuro Oda, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Masunori Matsuzaki.
  • 学会等名: 82nd Scientific Session of American Heart Association.
  • 発表場所: Orlando, USA.
  • 年月日: 2009-11-16
• [学会発表] Urine 8-hydroxy-2'-deoxyguanosine is Well Correlated With Cardiac Dysfunction and Poor Prognosis in Chronic Heart Failure Patients. (2009)
  • 著者名/発表者名: Takehisa Susa, Shigeki Kobayashi, Takeo Tanaka, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Yomoko Nao, Yasuhiro Yoshiga, Jutaro Yamada, Shuji Kawamura, Masafumi Yano, Masunori Matsuzaki.
  • 学会等名: 82nd Scientific Session of American Heart Association.
  • 発表場所: Orlando, USA.
  • 年月日: 2009-11-16
• [学会発表] Urine 8-hydroxy-2'-deoxyguanosine as a New Biomarker of Inflammatory Activity in Patients With Cardiac Sarcoidosis. (2009)
  • 著者名/発表者名: Takeo Tanaka, Shigeki Kobayashi, Takehisa Susa, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Tomoko Nao, Yasuhiro Yoshiga, Jutaro Yamada, Shuji Kawamura, Masafumi Yano, Masunori Matsuzaki.
  • 学会等名: 82nd Scientific Session of American Heart Association.
  • 発表場所: Orlando, USA.
  • 年月日: 2009-11-16
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