Exploration into the Development of New Therapy for Heart Failure by Modifying Sarcoplasmic Reticulum Nanodomain Function

• Project/Area Number: 19209030
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: MATSUZAKI Masunori Yamaguchi University, 大学院・医学系研究科, 教授 (60116754)
• Co-Investigator(Kenkyū-buntansha): IKEDA Yasuhiro 山口大学, 医学部, 講師 (00260349) ; YANO Masafumi 山口大学, 医学部・附属病院, 講師 (90294628) ; AOKI Hiroki 山口大学, 医学部, 准教授 (60322244) ; YAMAMOTO Takeshi 山口大学, 大学院・医学系研究科, 助教 (50363122) ; IZUMI Tomonori 山口大学, 大学院・医学系研究科, 准教授 (00261694) ; MAEKAWA Tsuyoshi 山口大学, 大学院・医学系研究科, 教授 (60034972)
• Research Collaborator: 青山 英和 山口大学, 大学院・医学系研究科, 大学院生 ; 宮崎 要介 山口大学, 大学院・医学系研究科, 大学院生 ; 藤本 静香 山口大学, 大学院・医学系研究科, 技術補佐員
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥50,700,000 (Direct Cost: ¥39,000,000、Indirect Cost: ¥11,700,000); Fiscal Year 2008: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000); Fiscal Year 2007: ¥37,440,000 (Direct Cost: ¥28,800,000、Indirect Cost: ¥8,640,000)
• Keywords: sarcoplasmic reticulum(SR) / shotgun proteomics / junctional SR / longitudinal SR / calcium / protein phosphatase / ryanodine receptor / protein phosphatase 1β

Research Abstract

重症心不全の心筋細胞でみられるCa^<2+>循環制御蛋白のリン酸化異常を惹起する分子機構を解明し、治療応用するための基盤的研究である。心筋から精製した筋小胞体(SR)再分画を使って、各ドメイン蛋白群(Ca^<2+>放出SR : Junctional SR、Ca^<2+>取り込みSR : Longitudinal SR)をそれぞれ同定し、リン酸化制御に関する主要蛋白の蛋白相互作用・機能解析を行った。また、その中でも最も重要な蛋白でCa^<2+>放出チャネルあるリアノジン受容体(RyR)について、機能安定化作用を有するアミノ酸配列を同定した。さらに筋小胞体表面の脱リン酸化調節をおこなう蛋白ホスファターゼ1の最も重要なアイソフォームを同定した。これら発見は心不全に対する分子標的療法を確立していくうえで重要な知見になると考えられた。

Research Products

• [Journal Article] Inhibitor-1 is Potential Target for Enhancing (2009)
  • Author(s): Ikeda Y, Yano M.
  • Journal Title: SarcoplasmicReticulum Ca(2+) Loading in Failing Hearts. Circ J. 73(6)(Editorial) Pages: 1018-9
• [Journal Article] Dantrolene, a therapeutic agent for malignant hyperthermia (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: markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. J Am Coll Cardiol 53(21) Pages: 1993-2005
• [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(1) 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
  • Journal Title: Cardiovascular Research 81 Pages: 536-545
  • Peer Reviewed
• [Journal Article] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca^<2+> leak in failing hearts (2008)
  • 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
• [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts (2008)
  • Author(s): Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M.
  • Journal Title: Circulation 117(6)(PubMed PMID : 18227387) Pages: 762-72
• [Journal Article] Enigma homolog 1 scaffolds protein kinase D1 to regulate the activity of the cardiac L-type voltage-gated calcium channel (2008)
  • Author(s): Maturana AD, Walchli S, Iwata M, Ryser S, Van Lint J, Hoshijima M, Schlegel W, Ikeda Y, Tanizawa K, Kuroda S.
  • Journal Title: Cardiovasc Res 78(3) Pages: 458-65
• [Journal Article] Identification and physiological activity of survival factor released from cardiomyocytes during ischaemia and reperfusion (2008)
  • Author(s): Mizukami Y, Ono K, Du CK, Aki T, Hatano N, Okamoto Y, Ikeda Y, Ito H, Hamano K, Morimoto S.
  • Journal Title: Cardiovasc Res 79(4) Pages: 589-99
• [Journal Article] Lentiviral Vector-mediated SERCA2 Gene Transfer Protects Against Heart Failure and Left Ventricular Remodeling After Myocardial Infarction in Rats (2008)
  • Author(s): Niwano K, Arai M, Koitabashi N, Watanabe A, Ikeda Y, Miyoshi H, Kurabayashi M.
  • Journal Title: Mol Ther (Epub ahead of print)
• [Journal Article] Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects (2008)
  • Author(s): Briggs LE, Takeda M, Cuadra AE, Wakimoto H, Marks MH, Walker AJ, Seki T, Oh SP, Lu JT, Sumners C, Raizada MK, Horikoshi N, Weinberg EO, Yasui K, Ikeda Y, Chien KR, Kasahara H.
  • Journal Title: Circ Res 103(6) Pages: 580-90
• [Journal Article] Role of ryanodine receptor as a Ca(2+) regulatory center in normal and failing hearts. (2008)
  • Author(s): Yano M
  • Journal Title: J Cardiol 53 Pages: 1-7
  • NAID: 10025182309
  • Peer Reviewed
• [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. (2008)
  • Author(s): Yamamoto T
  • Journal Title: Circulation 117 Pages: 762-72
  • Peer Reviewed
• [Journal Article] Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects. (2008)
  • Author(s): Briggs LE
  • Journal Title: Circulation Research 103 Pages: 580-590
  • Peer Reviewed
• [Journal Article] Identification and physiological activity of survival factor released from cardiomyocytes during ischaemia and reperfusion. (2008)
  • Author(s): Mizukami Y
  • Journal Title: Cardiovascular Research 73 Pages: 589-599
  • Peer Reviewed
• [Journal Article] Lentiviral vector-mediated SERCA2 gene transfer protects against heart failure and left ventricular remodeling after myocardial infarction in rats. (2008)
  • Author(s): Niwano K
  • Journal Title: Mol Ther. 16 Pages: 1026-32
  • Peer Reviewed
• [Journal Article] Toward biologically targeted therapy of calcium cycling defects in heart failure. (2008)
  • Author(s): Ikeda Y
  • Journal Title: Physiology 23 Pages: 6-16
  • Peer Reviewed
• [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correctchannel disorder in failing hearts. (2008)
  • Author(s): Yamamoto T
  • Journal Title: Circulation 117 Pages: 762-72
  • Peer Reviewed
• [Journal Article] Comparison of cell therapy and cytokine therapy for functional repair in ischemic and nonischemic heart failure (2007)
  • Author(s): Li TS, Mikamo A, Takahashi M, Suzuki R, Ueda K, Ikeda Y, Matsuzaki M, Hamano K.
  • Journal Title: Cell Transplant 16(4) Pages: 365-74
• [Journal Article] Progression of heart failure was suppressed by inhibition of apoptosis-signal regulating kinase (2007)
  • Author(s): Hikoso M, Ikeda Y, Yamaguchi O, Takeda T, Higuchi Y, Hirotani S, Kashiwase K, Yamada M, Asahi M, Matsumura Y, Nishida K, Matsuzaki M, Hori M, Otsu K.
  • Journal Title: 1(ASK-1) via transcoronary gene transferJ Am Coll Cardiol 50(5)(co-first author) Pages: 453-462
• [Journal Article] Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure (2007)
  • Author(s): Mochizuki M, Yano M, Oda T, Tateishi H, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M.
  • Journal Title: J Am Coll Cardiol 49(16) Pages: 1722-32
• [Journal Article] Progression of heart failure was suppressed by inhibition of apoptosis signal-regulating kinase 1 via transcoronary gene transfer. (2007)
  • Author(s): Hikoso S
  • Journal Title: J Am Coll Cardiol. 50 Pages: 453-62
  • Peer Reviewed
• [Journal Article] Comparison of cell therapy and cytokine therapy for functional repair in ischemicand nonischemic heart failure. (2007)
  • Author(s): Li TS
  • Journal Title: Cell Transplant. 16 Pages: 365-374
  • Peer Reviewed
• [Journal Article] Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. (2007)
  • Author(s): Mochizuki M
  • Journal Title: J Am Coll Cardiol. 49 Pages: 1722-32
  • Peer Reviewed
• [Presentation] Abstract 1533 : Protein Phosphatase 1 Beta is Most Abundan (2008)
  • Author(s): Aoyama H, Ikeda Y, Miyazaki Y, Ono M, Yoshimura K, Yamamoto T, Aoki H, Inui M, and Matsuzaki M
  • Organizer: Isoform in the Longitudinal Sarcoplasmic Reticulum and Regulates Phospholamban Phosphorylation in Cardiomyocytes Circulation
  • Place of Presentation: New Orleans、USA(118 : S_345-c-346S_-c)
• [Presentation] Abstract 1355 : The Vascular Smooth Muscle Cell-Autonomous Role of Id2 in Phenotypic Modulation In Vitro And (2008)
  • Author(s): Aoki H, Yoshimura K, Ikeda Y, and Matsuzaki M
  • Organizer: Atherogenesis In Vivo Circulation
  • Place of Presentation: New Orleans、USA(118 : S_312-a)
• [Presentation] Abstract 427 : c-Jun N-terminal Kinase 2 Translates Mechanical Stress to (2008)
  • Author(s): Yoshimura K, Aoki H, Kimura K, Ikeda Y, Aoyama H, Miyazaki Y, Morikage N, Furutani A, Hamano H, and Matsuzaki M
  • Organizer: Inflammatory Signal in Macrophages and Promotes Progression of Abdominal Aortic Aneurysm In Vivo Circulation
  • Place of Presentation: New Orleans、USA(118 : S_303-b)
• [Presentation] Abstract 5251 : Defective Inter-domain Interaction May Cause Spontaneous Ca^<2+> Release Via (2008)
  • Author(s): Ono M, Yano M, Suetomi T, Xu X, Uchinoumi H, Tateishi H, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, and Matsuzaki M
  • Organizer: Reduced Affinity of Calmodulin Binding to RyR2 in Failing Hearts Circulation
  • Place of Presentation: New Orleans、USA(118 : S_513-d-514S_ -d)
• [Presentation] Abstract 5272 : Perinatal Loss of Nkx2-5 Results in Rapid Conduction and Contraction Defects (2008)
  • Author(s): Briggs LE, Takeda M, Cuadra AE, Wakimoto H, Lu JT, Yasui K, Ikeda Y, Chien KR, and Kasahara H
  • Organizer: Circulation
  • Place of Presentation: New Orleans、USA(118 : S_517-a)
• [Presentation] Abstract 5289 : Abnormally Tight Domain-Domain Interaction at Mutation Site Could be a Primary Cause of Catecholaminergic Polymorphic Ventricular Tachycardia : Insight from RyR2^<S2246L/+> Knock-In Mouse (2008)
  • Author(s): Suetomi T, Yano M, Xu X, Ono M, Uchinoumi H, Tateishi H, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, and Matsuzaki M
  • Organizer: Model Circulation
  • Place of Presentation: New Orleans、USA(118 : S_520-b)
• [Presentation] Abstract 5303 : Decreased Affinity of Calmodulin Binding to RyR2 May Cause Leaky Channel in CPVT-Associated Mutation : Insight from RyR2^<R2474s/+> Knock-In Mouse Model (2008)
  • Author(s): Xu X, Yano M, Suetomi T, Ono M, Uchinoumi H, Tateishi H, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, and Matsuzaki M
  • Organizer: Circulation
  • Place of Presentation: New Orleans、USA(118 : S_523-a)
• [Presentation] Abstract 5322 : Mutation-Linked, Defective Inter-Domain Interaction within the Cardiac Ryanodine Receptor as a Critical Cause of (2008)
  • Author(s): Uchinoumi H, Yano M, Suetomi T, Xu Z, Ono M, Tateishi H, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, and Matsuzaki M
  • Organizer: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Circulation
  • Place of Presentation: New Orleans、USA(118 : S_526-b)
• [Presentation] Protein Phosphatase 1 Beta is Most Abundant Isoform in the Longitudinal Sarcoplasmic Reticulum and Regulates Phospholamban Phosphorylation in Cardiomyocytes (2008)
  • Author(s): Aoyama H
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Mutation-Linked, Defective Inter-Domain Interaction within the Cardiac Ryanodine Receptor as a Critical Cause of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2008)
  • Author(s): Uchinoumi H
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Decreased Affinity of Calmodulin Binding to RyR2 May Cause Leaky Channel in CPVT-Associated Mutation : Insight from RyR2^<R2474s/+> Knock-In Mouse Model (2008)
  • Author(s): Xu X
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Abnormally Tight Domain-Domain Interaction at Mutation Site Could be a Primary Cause of Catecholaminergic Polymorphic Ventricular Tachycardia : Insight from RyR2^<S2246L/+> Knock-In Mouse Model (2008)
  • Author(s): Suetomi T
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Defective Inter-domain Interaction May Cause Spontaneous Ca^<2+> Release Via Reduced Affinity of Calmodulin Binding to RyR2 in Failing Hearts (2008)
  • Author(s): Ono M
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] c-Jun N-terminal Kinase 2 Translates Mechanical Stress to Inflammatory Signal in Macrophages and Promotes Progression of Abdominal Aortic Aneurysm In Vivo (2008)
  • Author(s): Yoshimura K
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] The Vascular Smooth Muscle Cell-Autonomous Role of Id2 in Phenotypic Modulation In Vitro And Atherogenesis In Vivo (2008)
  • Author(s): Aoki H
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Protein phosphatase 1β is the major phospholamban phosphatase that regulates cardiac contractility in adult rat cardiomyocytes. (2007)
  • Author(s): Aoyama Hidekazu
  • Organizer: American Heart Association Annual Meeting
  • Place of Presentation: Orlando Convention Center,Florida,USA
  • Year and Date: 2007-11-06
• [Book] Oxford University Press (2008)
  • Author(s): Ikeda Y, Yamamoto T, Yano M, Matsuzaki M.
  • Publisher: Heart Failure Pathophyiology in Supportive Care for Cardiac Patient
• [Book] Supportive Care in Heart Failure (2008)
  • Author(s): Ikeda Y
  • Total Pages: 489
  • Publisher: Oxford University Press
• [Book] Heart Failure Pathophysiology in Supportive Care for Cardiac Patient (2008)
  • Author(s): Ikeda Y
  • Publisher: Oxford University Press(In print)
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