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

2010 Fiscal Year Final Research Report

• 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
• 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

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
  • 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] 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
• [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] 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 Pages: A22-A30
• [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.
  • Year and Date: 20090800
• [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
  • Year and Date: 20090700
• [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
• [Remarks] ホームページ等 なし