Development of new therapy for heart failure and arrhythmia by correction of signal transduction within cardiac ryanodine receptor

• Project/Area Number: 20390226
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YANO Masafumi Yamaguchi University, 医学部・附属病院, 講師 (90294628)
• Co-Investigator(Kenkyū-buntansha): IKEDA Yasuhiro 山口大学, 大学院・医学系研究科, 助教 (00260349) ; KOBAYASHI Shigeki 山口大学, 医学部・附属病院, 助教 (90397993)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2010: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2009: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2008: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
• Keywords: 筋小胞体 / カルシウム / 心不全 / 致死的不整脈 / リアノジン受容体 / 点突然変異

Research Abstract

The defective inter-domain interaction between N-terminal and central domains within RyR2 reduces the binding affinity of CaM to RyR2, thereby causing the spontaneous Ca^<2+> release events in diseased hearts. Correction of the defective CaM binding may be a new strategy to protect against the aberrant Ca^<2+> release in heart failure and lethal arrhythmia.

Research Products

• [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure. (2011)
  • Author(s): 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.
  • Journal Title: Eur J Heart Fail. 13 Pages: 29-36
• [Journal Article] Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2^<R2474S/+> knock-in mouse model. (2010)
  • Author(s): 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.
  • Journal Title: Circ J. 74 Pages: 2579-2584
  • NAID: 10027424202
  • Peer Reviewed
• [Journal Article] Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure. (2010)
  • Author(s): 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.
  • Journal Title: Cardiovasc Res. 87(4) Pages: 609-617
  • Peer Reviewed
• [Journal Article] Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. (2010)
  • Author(s): 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.
  • Journal Title: Biochem Biophys Res Commun. 394 Pages: 660-666
  • Peer Reviewed
• [Journal Article] Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor. (2010)
  • Author(s): 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.
  • Journal Title: Circ Res. 106 Pages: 1413-1424
  • Peer Reviewed
• [Journal Article] Polymorphic Ventricular Tachycardia Is Caused by Mutation-Linked Defective Conformational Regulation of the Ryanodine Receptor. (2010)
  • Author(s): Hitoshi Uchinoumi
  • Journal Title: Circulation Research Volume: 106 Pages: 1413-1424
  • Peer Reviewed
• [Journal Article] Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. (2010)
  • Author(s): Xiaojuan Xu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 394 Pages: 660-666
  • Peer Reviewed
• [Journal Article] Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure. (2010)
  • Author(s): Makoto Ono
  • Journal Title: Cardiovascular Research Volume: 87 Pages: 609-617
  • Peer Reviewed
• [Journal Article] Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2(R2474S/+)Knock-In Mouse Model. (2010)
  • Author(s): Shigeki Kobayashi
  • Journal Title: Circulation Journal Volume: 74 Pages: 2579-2584
  • NAID: 10027424202
  • Peer Reviewed
• [Journal Article] Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. (2009)
  • Author(s): Kobayashi S, Yano M, Suetomi T, Ono M, Tateishi H, Mochizuki M, Xu X, Uchinoumi H, Okuda S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M.
  • Journal Title: J Am Coll Cardiol. 53 Pages: 1993-2005
  • Peer Reviewed
• [Journal Article] Role of ryanodine receptor as a Ca(2+) regulatory center in normal and failing hearts. (2009)
  • Author(s): Yano M, Yamamoto T, Kobayashi S, Matsuzaki M.
  • Journal Title: J Cardiol. 53 Review Pages: 1-7
  • NAID: 10025182309
• [Journal Article] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • Author(s): 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.
  • Journal Title: Cardiovasc Res. 81 Pages: 536-545
  • Peer Reviewed
• [Journal Article] Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. (2009)
  • Author(s): Shigeki Kobayashi
  • Journal Title: Journal of American College of Cardiology 53 Pages: 1993-2005
  • Peer Reviewed
• [Journal Article] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • Author(s): Hiroki Tateishi
  • Journal Title: Cardiovascular Research 81 Pages: 536-45
  • Peer Reviewed
• [Journal Article] Defective Ca2+ cycling as a key pathogenic mechanism of heart failure. (2008)
  • Author(s): Yano M, Yamamoto T, Kobayashi S, Ikeda Y, Matsuzaki M.
  • Journal Title: Circ J. 72 Suppl A Review
  • NAID: 110006935628
• [Journal Article] Role of ryanodine receptor as a Ca(2+) regulatory center innormal and failing hearts. (2008)
  • Author(s): Masafumi Yano
  • Journal Title: Journal of Cardiology 53 Pages: 1-7
• [Presentation] Mutation-linked Defective Domain Interaction within the Ryanodine Receptor Causes Ca2+ Leak Leading to Catecholaminergic Polymorphic Ventricular Tachycardia (2010)
  • Author(s): Takeshi Suetomi
  • Organizer: American Heart Association, Scientific sessions 2010
  • Place of Presentation: Chicago
  • Year and Date: 2010-11-17
• [Presentation] Correction of Defective Calmodulin Binding to Cardiac Ryanodine Receptor Inhibits Aberrant Ca2+ Release in CPVT-associated Mutation (2010)
  • Author(s): Masakazu Fukuda
  • Organizer: American Heart Association, Scientific sessions 2010
  • Place of Presentation: Chicago
  • Year and Date: 2010-11-17
• [Presentation] Increased Affinity of Calmodulin Binding to Cardiac Ryanodine Receptor Corrects the Defective Channel Gating in Failing Hearts (2010)
  • Author(s): Akihiko Hino
  • Organizer: American Heart Association, Scientific sessions 2010
  • Place of Presentation: Chicago
  • Year and Date: 2010-11-16
• [Presentation] Interruption of Novel Inter-domain Interaction Within RyR2 as a Common Therapeutic Target by Channel Stabilization in Heart Failure and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2010)
  • Author(s): Takeshi Yamamoto
  • Organizer: American Heart Association, Scientific sessions 2010
  • Place of Presentation: Chicago
  • Year and Date: 2010-11-15
• [Presentation] A genetically modified mouse model to better understand catecholaminergic polymorphic ventricular tachycardia. (symposium) (2009)
  • Author(s): Yano M.
  • Organizer: ESC congress.
  • Place of Presentation: Barcelona, Spain.
• [Presentation] Ryanodine Receptor Defects in Heart Failure and Lethal Arrhythmia (2009)
  • Author(s): Yano M.
  • Organizer: Basic Cardiovascular Sciences Conference (American Heart Association)
  • Place of Presentation: Las Vegas, Nevada, USA
• [Presentation] A genetically modified mouse model to better understand catecholaminergic Polymorphic Ventricular Tachycardia (2009)
  • Author(s): Masafumi Yano
  • Organizer: European Society of Cardiology Congress 2009, Barcelona, 2009. 8
  • Place of Presentation: Barcelona, Spain
• [Presentation] A genetically modified mouse model to better understand catecholaminergic Polymorphic Ventricular Tachycardia (2009)
  • Author(s): Masafumi Yano
  • Organizer: Basic Cardiovascular Sciences Annual Conference (American Heart Association) 2009
  • Place of Presentation: Las Vegas, USA
• [Presentation] Abnormal Ryanodine Receptor Function in Heart Failure. (2008)
  • Author(s): Yano M.
  • Organizer: Basic Cardiovascular Sciences Conference (American Heart Association)
  • Place of Presentation: Keystone, Co, USA
  • Year and Date: 2008-07-30
• [Presentation] Abnormal Ryanodine Receptor Function in Heart Failure. (2008)
  • Author(s): Masafumi Yano
  • Organizer: Basic Cardiovascular Sciences Conference 2008 (American Heart Association)
  • Place of Presentation: Keystone, Co, USA
  • Year and Date: 2008-07-30
• [Remarks] ホームページ等 なし