Molecular mechanism of contractile dysfunction and the alteration of intracellular Ca^<2+> handling caused by mutation of cardiac troponin T

2009 Fiscal Year Final Research Report

• Project/Area Number: 19500357
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurophysiology and muscle physiology
• Research Institution: Jikei University School of Medicine
• Principal Investigator: KURIHARA Satoshi Jikei University School of Medicine, 医学部, 教授 (90057026)
• Co-Investigator(Kenkyū-buntansha): HONGO Kenichi 東京慈恵会医科大学, 医学部, 准教授 (00256447) ; KOMUKAI Kimiaki 東京慈恵会医科大学, 医学部, 講師 (60360145) ; SASAKI Hiroyuki 東京慈恵会医科大学, 医学部, 准教授 (60170693) ; FUKUDA Norio 東京慈恵会医科大学, 医学部, 講師 (30301534) ; MORIMOTO Sachio 九州大学, 医学研究科, 准教授 (50202362)
• Project Period (FY): 2007 – 2009
• Keywords: 心筋 / トロポニンT / Ca^<2+>感受性 / アンギオテンシンII受容体 / Ca^<2+>

Research Abstract

We explored the mechanism of pathogenesis and sudden death in dilated cardiomyopathy using knock-in mouse model with mutant troponin T (DCM mouse). DCM mouse died suddenly from age of 1 month old. In DCM mouse, cardiac chamber was dilated and contractile functions were impaired. A blocker of angiotensin II receptor (ARB) significantly increased survival rate and improved the cardiac functions without changing the decreased Ca^<2+> sensitivity in DCM mouse. ARB also improved the fibrosis and electrocardiogram, which were considered as critical for the beneficial effects of ARB.

Research Products

• [Journal Article] Titin and troponin : central players in the Frank-Starling mechanism ofthe heart. (2009)
  • Author(s): Fukuda N, Terui T, Ohtsuki I, Ishiwata S, Kurihara S
  • Journal Title: Current Cardiology Reviews 5(2) Pages: 119-124
  • Peer Reviewed
• [Journal Article] Half-logistic time constants as inotropic and lusitropic indices for four sequential phases of isometric tension curves in isolated rabbit and mouse papillary muscles. (2009)
  • Author(s): Mizuno J, Morita S, Otsuji M, Arita H, Hanaoka K, Robert E, Hirano S, Kusakari Y, Kurihara S
  • Journal Title: Int Heart J 50(3) Pages: 389-404
  • Peer Reviewed
• [Journal Article] Protein kinase A-dependent modulation of Ca2+ sensitivity in cardiac and fast skeletal muscles after reconstitution with cardiac troponin (2009)
  • Author(s): Matsuba D, Terui T, O-Uchi J, Tanaka H, Ojima T, Otsuki I, Ishiwata, Kurihara S, Fukuda N
  • Journal Title: J Gen Physiol 133(6) Pages: 571-581
  • Peer Reviewed
• [Journal Article] Protein kinase A-dependent phosphorylation of ryanodine receptors increases Ca2+ leak in mouse heart (2009)
  • Author(s): Morimoto S, O-Uchi J, Kawai M, Hoshina T, Kusakari Y, Komukai K, Sasaki H, Hongo K, Kurihara S
  • Journal Title: BBRC 390 Pages: 87-92
  • Peer Reviewed
• [Journal Article] 左室圧、張力、筋細胞内カルシウムトランジェントのハイブリッド・ロジスティック関数を用いた波形解析による収縮弛緩過程の推定 (2009)
  • Author(s): 水野樹、森田茂穂、大辻幹哉、花岡一雄、栗原敏
  • Journal Title: 臨床麻酔 33(9) Pages: 1479-1488
  • Peer Reviewed
• [Journal Article] Interaction of alpha1-adrenoceptor subtypes with different G proteins induces opposite effects on cardiac L-type Ca2 channel (2008)
  • Author(s): O-Uchi J, Sasaki H, Morimoto S, Kusakari Y, Shinji H, Obata T, Hongo K, Komukai K, Kurihara S
  • Journal Title: Circ Res 102(11) Pages: 1378-1388
  • Peer Reviewed
• [Journal Article] Physiological functions of the giant elastic protein titin in mammalian striated muscle (2008)
  • Author(s): Fukuda N, Granzier HL, Ishiwata S, Kurihara S
  • Journal Title: J Physiol Sci 58(3) Pages: 151-159
  • Peer Reviewed
• [Presentation] Endothelin-1 increases L-type Ca2+ current of rat ventricular myocytes via an activation of protein kinase C and Ca2+/calmodulin dependent protein kinaseII (2009)
  • Author(s): Komukai K, O-Uchi J, Hongo K, Kawai M, Morimoto S, Yoshimura M, Kurihara S
  • Organizer: American Heart Association
  • Place of Presentation: Orlando, USA
  • Year and Date: 20091114-20091118
• [Presentation] トロポニン再構成によるFrank-Starling機構の分子メカニズムの解明 (2009)
  • Author(s): 照井貴子、福田紀男、大槻磐男、上園晶一、栗原敏
  • Organizer: 日本麻酔科学会第56回学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20090817-20090818
• [Presentation] Renin-angiotensin system plays an important role in the pathogenesis of DCM in mouse (2009)
  • Author(s): Hongo K, Morimoto S, O-Uchi J, Kusakari Y, Komukai K, Kawai M, Yoshimura M, Morimoto S, Ohtsuki I, Takeda N, Kurihara S
  • Organizer: The XXXVI International Congress of Physiological Sciences
  • Place of Presentation: 京都
  • Year and Date: 20090727-20090801
• [Presentation] Endothelin-1 potentiates L-type Ca2+ current by activating CaMKII in rat ventricular myocytes (2009)
  • Author(s): Komukai K, O-uchi J, Morimoto S, Kawai M, Hongo K, Yoshimura M, Kurihara S
  • Organizer: The XXXVI International Congress of Physiological Sciences
  • Place of Presentation: 京都
  • Year and Date: 20090727-20090801
• [Presentation] β-Adrenoceptor stimulation increased Ca2+ leak from sarcoplasmic reticulum without dissociation of FKBP12. 6 under physiological condition (2009)
  • Author(s): Morimoto S, O-uchi J, Kawai M, Komukai K, Sasaki H, Yoshimura M, Hongo K, Kurihara S
  • Organizer: The XXXVI International Congress of Physiological Sciences
  • Place of Presentation: 京都
  • Year and Date: 20090727-20090801
• [Presentation] Thin filament-based regulation of length-dependent activation in skinned porcine ventricular muscle (2009)
  • Author(s): Terui T, Shimamoto Y, Sodnomtseren M, Yamane M, Ohtsuki I, Ishiwata S, Kurihara S, Fukuda N
  • Organizer: The XXXVI International Congress of Physiological Sciences
  • Place of Presentation: 京都
  • Year and Date: 20090727-20090801
• [Presentation] Microscopic analysis of sarcomeric oscillatioins by quantum dots in skinned rat ventricular myocytres (2008)
  • Author(s): Serizawa T, O-Uchi J, Fukuda N, Kurihara S, Ishiwata S
  • Organizer: 第46回日本生物物理学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20081203-20081205
• [Presentation] Decreased Ca2+ affinity of thin filament is an important factor for the development of cardiac dysfunction in mouse model of dilated cardiomyopathy (2008)
  • Author(s): O-Uchi J, Hongo K, Morimoto S, Komukai K, Kawai M, Ohtsuki I, Morimoto S, Kurihara S
  • Organizer: Thick and thin filament regulation in striated muscle
  • Place of Presentation: Madison, USA
  • Year and Date: 20080504-20080506
• [Presentation] Thin filament-based regulation of length dependent activation in skinned porcine ventricular muscle (2008)
  • Author(s): Terui Y, Sodnomtseren M, Ishiwata S, Ohtsuki I, Fukuda N, Kurihara S
  • Organizer: 第31回心筋代謝研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-07-13
• [Presentation] Molecular basis for the Frank-Starli-ng mechanism of the heart (2008)
  • Author(s): Kurihara S, Fukuda N, Ohtsuki I, Terui T, Hongo K, Komukai K, Ishikawa T
  • Organizer: 心臓循環器系調節機構の病態生理学に関する国際シンポジウム
  • Place of Presentation: 山形
  • Year and Date: 2008-05-24
• [Presentation] Decreased Ca2+ sensitivity of the myofilament is critcal for the development of cardiac dysfunction in mouse model of dilated cardiomyopathy (2008)
  • Author(s): Hongo K, (Kurihara S)
  • Organizer: 第72回日本循環器学会総会・学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2008-03-28
• [Presentation] Altered Ca2+ handling could contribute to the cardiac sudden death in knock-in mouse of dilated cardiomyopathy (2007)
  • Author(s): Hongo K, (Kurihara S)
  • Organizer: 第30回心筋代謝研究会
  • Place of Presentation: 京都
  • Year and Date: 2007-07-15
• [Presentation] Changes in Ca2+ transient and contraction of left ventricular papillary muscles in mouse model of dilated cardiomyopathy (2007)
  • Author(s): Hongo K, (Kurihara S)
  • Organizer: The 24th annual meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: Ferrara, Italy
  • Year and Date: 2007-06-21