Development of therapeutic therapy for regression of cardiac hypertrophy in hypertrophic cardiomyopathy

• Project/Area Number: 22659154
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YANO Masafumi 山口大学, 医学部附属病院, 講師 (90294628)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Takeshi 山口大学, 大学院・医学系研究科, 助教 (50363122) ; IKEDA Yasuhiro 山口大学, 大学院・医学系研究科, 助教 (00260349)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,160,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: 肥大型心筋症 / カルシウムハンドリング / リアノジン受容体 / カルシウム動態 / 筋小胞体 / カルシウム / 心不全 / 致死的不整脈 / 点突然変異

Research Abstract

Hypertrophic cardiomyopathy(HCM) is known to be a myocardial disorder characterized by idiopathic hypertrophy of the left ventricule. In HCM patients, sudden death occurs owing to lethal arrhythmia in young age and diastolic heart failure can be sometimes developed. Medical approach for regression of hypertrophy in HCM patients remains elusive. Here, we hypothesized that diastolic Ca2+ leak through ryanodine receptor(RyR2) might predispose to abnormal hypertrophy in HCM patients. To verify this hypothesis, we investigated the pathogenic role of Ca2+ leak through RyR2 in transgenic mouse(TG) model of familial hypertrophic cardiomyopathy-related cardiac troponin T mutation. Diastolic Ca2+ leak through defective RyR2 is induced by beta-adrenergic stimulation in TG cardiomyocytes. Dantrolene, which was found to stabilize RyR2 inhibited Ca2+ leak. These results suggest that stabilization of RyR2 and subsequent inhibition of Ca2+ leak might play a pivotalrole for regression of abnormal hypertrophy in HCM patients.

Research Products

• [Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca^<2+> release leading to catecholaminergic polymorphic (2011)
  • Author(s): 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.
  • Journal Title: ventricular tachycardia. Circulation Volume: 124(6) Pages: 682-94
  • Peer Reviewed
• [Journal Article] Urinary8-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 Volume: 13(1) Pages: 29-36
  • Peer Reviewed
• [Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca^<2+> release leading to catecholaminergic polymorphic ventricular tachycardia (2011)
  • Author(s): Takeshi Suetomi
  • Journal Title: Circulation Volume: 124 Issue: 6 Pages: 682-694
  • DOI: 10.1161/circulationaha.111.023259
  • Peer Reviewed
• [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure (2011)
  • Author(s): Shigeki Kobayashi
  • Journal Title: European Journal of Heart Faililure Volume: 13 Issue: 1 Pages: 29-36
  • DOI: 10.1093/eurjhf/hfq178
  • Peer Reviewed
• [Journal Article] Matsuzaki M. Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic (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
  • Journal Title: Polymorphic Ventricular Tachycardia in a RyR2(R2474S/+) Knock-In Mouse Model. Circ J Volume: 74 Pages: 2579-84
  • 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 Volume: 394 Pages: 660-6
  • Peer Reviewed
• [Journal Article] Catecholaminergic Polymorphic Ventricular Tachycardia Is Caused by Mutation-Linked Defective Conformational Regulation of the (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: Ryanodine Receptor. Cir Res Volume: 106 Pages: 1413-24
  • Peer Reviewed
• [Journal Article] Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ releasein 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 Volume: 87 Pages: 609-17
  • 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
  • Peer Reviewed
• [Presentation] Coupled Conformational Changes in the Local and Global Inter-Domain Interactions Trigger Diastolic Ca2+ Release and Lethal Arrhythmia in Catecholaminergic Polymorphic Ventricular Tachycardia(CPVT) (2011)
  • Author(s): Suetomi T, Yano T, Kato T, Fukuda M, Hino A, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Matsuzaki M
  • Organizer: American Heart association Scientific meeting 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-15
• [Presentation] Enhancement of Calmodulin Binding to RyR2 Inhibits Aberrant Ca2+ Release in CPVT-Associated Mutation (2011)
  • Author(s): Masakazu Fukuda
  • Organizer: American Heart association Scientific meeting 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-15
• [Presentation] Matsuzaki M. Enhancement of Calmodulin Binding to RyR2 Inhibits Aberrant Ca2+ Release in CPVT-Associated Mutation (2011)
  • Author(s): Fukuda M, Yano M, Kato T, Hino A, Suetomi T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T
  • Organizer: American Heart association Scientific meeting
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-14
• [Presentation] Urinary 8-hydroxy-2'-deoxyguanosine as a Novel Biomarker of Inflammatory Activity in Patients with Cardiac Sarcoidosis : Insight From Immunohistochemical Technique and 18F-FDG PET/ CT (2011)
  • Author(s): Fukuta S, Kobayashi S, Tanaka T, Susa T, Murakami W, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Ueyama T, Okamura T, Kawamura S, Yano M, Matsuzaki M
  • Organizer: American Heart association Scientific meeting 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-14
• [Presentation] Urinary 8-hydroxy-2'-deoxyguanosine as a Novel Biomarker of Activity in Patients with Cardiac Sarcoidosis : Insight From Immunohistochemical Technique and 18F-FDG PET/CT (2011)
  • Author(s): Seiko Fukuta
  • Organizer: American Heart association Scientific meeting 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-14
• [Presentation] Structure-based drug design to modulate RyR2 function (2011)
  • Author(s): Yano M.
  • Organizer: American Heart association Scientific meeting 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-13
• [Presentation] Structure-based drug design to modulate RyR2 function (2011)
  • Author(s): Masafumi Yano
  • Organizer: American Heart association Scientific meeting 2011
  • Place of Presentation: Orland, USA(招待講演)
  • Year and Date: 2011-11-13
• [Presentation] Conformational Changes in the Local and Global Inter-Domain Interactions Trigger Diastolic Ca2+ Release and Lethal Arrhythmia in Tachycardia Catecholaminergic Polymorphic Ventricular (CPVT) (2011)
  • Author(s): Takeshi Suetomi
  • Organizer: American Heart association Scientific meeting 2011
  • Place of Presentation: Orland, USA
  • Year and Date: 2011-11-13
• [Presentation] Correction of Defective Calmodulin Binding to Cardiac Ryanodine Receptor Inhibits Aberrant Ca2+ Release in CPVT-associated Mutation (2010)
  • Author(s): Fukuda M, Yano M, Hino A, Suetomi T, Xu X, Ono M, Uchinoumi H, Doi M, Okuda S, Kobayashi S, Yamamoto T, Matsuzaki M
  • Organizer: Inhibits Aberrant Ca^<2+> Release in CPVT-associated Mutation American Heart association Scientific meeting 2010
  • Place of Presentation: Chicago, USA
  • Year and Date: 2010-11-17
• [Presentation] Mutation-linked Defective Domain Interaction within the Ryanodine Receptor Causes Ca^<2+> Leak Leading to Catecholaminergic Polymorphic Ventricular Tachycardia (2010)
  • Author(s): Suetomi T, Yano M, Fukuda M, Hino A, Ono M, Xu X, Susa T, Uchinoumi H, Oda T, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Matsuzaki M
  • Organizer: American Heart association Scientific meeting 2010
  • Place of Presentation: Chicago, USA
  • Year and Date: 2010-11-17
• [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): Hino A, Yano M, Fukuda M, Suetomi T, Ono M, Xu X, Uchinoumi H, Susa T, Doi M, Okuda S, Kobayashi S, Yamamoto T, Matsuzaki M
  • Organizer: American Heart association Scientific meeting 2010
  • Place of Presentation: Chicago, USA
  • Year and Date: 2010-11-16
• [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] Correction of Defective Inter-domain Interaction Within the Cardiac Ryanodine Receptor as a New Therapeutic Strategy Against Catecholaminergic Polymorphic Ventricular Tachycardia(CPVT) (2009)
  • Author(s): Uchinoumi H, Yano M, Hino A, Suetomi T, Ono M, Xu X, Oda T, Doi M, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Matsuzaki M
  • Organizer: American Heart association Scientific meeting 2009
  • Place of Presentation: Orlando, USA
  • Year and Date: 2009-11-18
• [Presentation] Low-dose ofβBlocker Improves Cardiac Function in Patients With Acute Heart Failure Partly by Inhibiting Ca^<2+> Leak Through the Ryanodine Receptor (2009)
  • Author(s): Kobayashi S, Tanaka T, Susa T, Ono M, Uchinoumi H, Okuda S, Doi M, Kawamura S, Yamamoto T, Yano M, Matsuzaki M.
  • Organizer: American Heart association Scientific meeting 2009
  • Place of Presentation: Orlando, USA
  • Year and Date: 2009-11-18
• [Presentation] Mutation-linked Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia(CPVT) is Caused by Abnormally Tight Domain-Domain (2009)
  • Author(s): Suetomi T, Yano M, Hino A, Ono M, Xu X, Susa T, Uchinoumi H, Oda T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Matsuzaki M
  • Organizer: Interaction in RyR2 American Heart association Scientific meeting 2009
  • Place of Presentation: Orlando, USA
  • Year and Date: 2009-11-17
• [Presentation] Decreased Affinity of Calmodulin to RyR2 May Be a Sauce Mechanism of Leaky Channel in CPVT-associated Mutation (2009)
  • Author(s): Xu X, Yano M, Hino A, Suetomi T, Ono M, Uchinoumi H, Oda T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Ohkusa T, Matsuzaki M
  • Organizer: American Heart association Scientific meeting 2009
  • Place of Presentation: Orlando, U. S. A.
  • Year and Date: 2009-11-16
• [Book] シグナル伝達系からみた心不全の機序と治療戦略, Cardioligy Frontier (2011)
  • Author(s): 奥田真一、矢野雅文
  • Publisher: メディカルレビュー社
• [Book] 慢性心不全の治療;Medicament News (2011)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 3
  • Publisher: ライフサイエンス
• [Book] シグナル伝達系からみた心不全の機序と治療戦略;Cardioligy Frontier (2011)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 8
  • Publisher: ライフサイエンス
• [Book] 慢性心不全治療ガイドライン;冠動脈疾患下巻 (2011)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 10
  • Publisher: 日本臨床社
• [Book] 不全心筋における逆リモデリングの分子生物学的機序,呼吸と循環 (2010)
  • Author(s): 奥田真一、矢野雅文
  • Publisher: 医学書院