Molecular mechanisms of an improvement in prognosis in the mouse model of dilated cardiomyopathy treated by inhibition of the RAA system

2012 Fiscal Year Final Research Report

• Project/Area Number: 22300130
• Research Category: Grant-in-Aid for Scientific Research (B)
• 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 東京慈恵会医科大学, 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) ; SASAKI Hiroyuki 東京慈恵会医科大学, 医学部, 准教授 (60170693) ; KOMUKAI Kimiaki 東京慈恵会医科大学, 医学部, 講師 (60360145) ; KUSAKARI Yoichiro 東京慈恵会医科大学, 医学部, 講師 (80338889)
• Co-Investigator(Renkei-kenkyūsha): MORIMOTO Sachio 東京慈恵会医科大学, 医学部, 准教授 (50202362)
• Project Period (FY): 2010 – 2012
• Keywords: 細胞内Ca^<2+> / トロポニン / Ca^<2+>感受性 / アンギオテンシン / 拡張型心筋症

Research Abstract

We investigated the role of the renin-angiotensin-aldosterone system (RAA system) on the dilated cardiomyopathy, to clarify the molecular mechanism and morphological changes in heart failure.By inhibition of the RAA system, survival rate of the mouse model of dilated cardiomyopathy was significantly improved. We conclude that the possible mechanisms of RAA inhibition for improving life-span of dilated cardiomyopathy should include (1) inhibition of fibrosis and (2) an enhancement of contractility without improvement of the Ca_ sensitivity.

Research Products

• [Journal Article] Alpha_1-adrenenoceptor stimulation inhibits cardiac excitation-contraction coupling through tyrosine phosphorylation of beta_1-adrenoceptor (2013)
  • Author(s): O-Uchi J, Komukai K, Kusakari Y, Morimoto S, Kawai M, Jhun BS, Hurst S, Hongo K, Sheu SS, Kurihara S
  • Journal Title: Biochem Biophys Res Commun Volume: 433(2) Pages: 188-93
  • DOI: doi:10.1016/j.bbrc.2013.02.072
  • Peer Reviewed
• [Journal Article] Sarcomere imaging by quantum dots for the study of cardiac muscle physiology (2012)
  • Author(s): Kobirumaki-Shimozawa F, Oyama K, Serizawa T, Mizuno A, Kagemoto T, Shimozawa T, Ishiwata S, Kurihara S, Fukuda N
  • Journal Title: J Biomed Biotechnol Pages: 313814
  • DOI: doi:10.1155/2012/313814
  • Peer Reviewed
• [Journal Article] Role of Ca^ in the rapid cooling-induced Ca^ release from sarcoplasmic reticulum in ferret cardiac muscles (2012)
  • Author(s): Tanaka E, Konishi M, Kurihara S
  • Journal Title: J Physiol Sci Volume: 62(3) Pages: 241-50
  • DOI: doi:10.1007/s12576-012-0203-1
  • Peer Reviewed
• [Journal Article] Sarcomere length-dependent Ca^ activation in skinned rabbit psoas muscle fibers: coordinated regulation of thin filament cooperative activation and passive force (2011)
  • Author(s): Fukuda N, Inoue T, Yamane M, Terui T, Kobirumaki F, Ohtsuki I, Ishiwata S, Kurihara S
  • Journal Title: J Physiol Sci Volume: 61(6) Pages: 515-23
  • DOI: doi:10.1007/s12576-011-0173-8
  • Peer Reviewed
• [Journal Article] Real-time measurement of the length of a single sarcomere in rat ventricular myocytes: a novel analysis with quantum dots (2011)
  • Author(s): Serizawa T, Terui T, Kagemoto T, Mizuno A, Shimozawa T, Kobirumaki F, Ishiwata S, Kurihara S, Fukuda N
  • Journal Title: Am J Physiol Cell Physiol Volume: 301(5) Pages: C1116-27
  • DOI: doi:10.1152/ajpcell.00161.2011
  • Peer Reviewed
• [Journal Article] Depressed contractile performance and reduced fatigue resistance in single skinned fibers of soleus muscle after long-term disuse in rats (2011)
  • Author(s): Udaka J, Terui T, Ohtsuki I, Marumo K, Ishiwata S, Kurihara S, Fukuda N
  • Journal Title: J Appl Physiol Volume: 111(4) Pages: 1080-7
  • DOI: doi:10.1152/japplphysiol.00330.2011
  • Peer Reviewed
• [Journal Article] Regulatory mechanism of length-dependent activation in skinned porcine ventricular muscle: role of thin filament cooperative activation in the Frank-Starling relation (2010)
  • Author(s): Terui T, Shimamoto Y, Yamane M, Kobirumaki F, Ohtsuki I, Ishiwata S, Kurihara S, ・Fukuda N
  • Journal Title: J Gen Physiol Volume: 136(4) Pages: 469-82
  • DOI: doi:10.1085/jgp.201010502
  • Peer Reviewed
• [Journal Article] Titin-based regulations of diastolic and systolic functions of mammalian cardiac muscle (2010)
  • Author(s): Fukuda N, Terui T, Ishiwata S, Kurihara S
  • Journal Title: J Mol Cell Cardiol Volume: 48(5) Pages: 876-81
  • DOI: doi:10.2174/157340309788166714
  • Peer Reviewed
• [Journal Article] Role of Ca^/calmodulin-dependent protein kinase II in the regulation of the cardiac L-type Ca^current during endothelin-1 stimulation (2010)
  • Author(s): Komukai K, O-Uchi J, Morimoto S, Kawai M, Hongo K, Yoshimura M, Kurihara S
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 298(6) Pages: H1902-7
  • DOI: doi:10.1152/ajpheart.01141.2009
  • Peer Reviewed
• [Presentation] Real-time imaging of single sorcomeres in the mouse heart in vivo (2013)
  • Author(s): Kobirumaki-Shimozawa F, Oyama K, Mizuno A, Terui T, Shimozawa T, Ishiwata S, Kurihara S, Fukuda N
  • Organizer: 第90回日本生理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130300
• [Presentation] Impairment of E-C coupling in cardiac papillary muscle with fibrosis (2013)
  • Author(s): Kusakari Y, Urashima T, Minamisawa S, Kurihara S
  • Organizer: 第90回日本生理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130300
• [Presentation] Depressed length-dependent activation in left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation K210 (2013)
  • Author(s): Inoue T, Kobirumaki-Shimozawa F, Kagemoto T, Fujii T, Terui T, Kusakari Y, Hongo K, Morimoto S, Ohtsuki I, Kurihara S, Fukuda N
  • Organizer: 第90回日本生理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130300
• [Presentation] Selective modulation of SERCA did not affect Ca^ leak from sarcoplasmic reticulum in transgenic mouse models (2012)
  • Author(s): Morimoto S, Hongo K, Kusakari Y, Komukai K, Kawai M, Yoshimura M, Kurihara S
  • Organizer: Scientific session of American Heart Association
  • Place of Presentation: Los Angeles, CA, USA
  • Year and Date: 20121100
• [Presentation] Estimation of E-C coupling in cardiac papillary muscle with fibrosis (2012)
  • Author(s): Kusakari Y, Urashima T, Kurihara S, Minamisawa S
  • Organizer: The 29th Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 福岡
  • Year and Date: 20121000
• [Presentation] Auto-oscillation (SPOC) properties of sarcomeres in rat neonatal cardiomyocytes (2012)
  • Author(s): Shintani S, Yamane M, Oyama K, Kurihara S, Fukuda N, Ishiwata S
  • Organizer: 第50回日本生物物理学会
  • Place of Presentation: 名古屋
  • Year and Date: 20120900
• [Presentation] 心筋線維化における興奮収縮連関 (2012)
  • Author(s): 草刈洋一郎,浦島崇,栗原敏
  • Organizer: 第16回日本適応医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20120600
• [Presentation] Compensatory increase in the Ca^ transient is important for contractile recovery of dilated cardiomyopathy in mice (2012)
  • Author(s): Hongo K, Morimoto S, Kusakari Y, Komukai K, Kawai M, Yoshimura M, Kurihara S
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 20120300
• [Presentation] Impairment of E-C coupling in cardiac papillary muscle with fibrosis induced by pressure overload (2012)
  • Author(s): Kusakari Y, Urashima T, Kurihara S
  • Organizer: 第89回日本生理学会学術集会
  • Place of Presentation: 松本
  • Year and Date: 20120300
• [Presentation] Depressed length-dependent activation in skinned left ventricular muscles from a mouse model of dilated cardiomyopathy (2012)
  • Author(s): Inoue T, Kusakari Y, Hongo K, Morimoto S, Ohtsuki I, Kurihara S, Fukuda N
  • Organizer: 第89回日本生理学会学術集会
  • Place of Presentation: 松本
  • Year and Date: 20120300
• [Presentation] Properties of sarcomeric self-oscillations in rat neonatal cardiomyocytes: Relationship with heart beats by responce of electrical stimuli (2012)
  • Author(s): Shintani S, Yamane M, Oyama K, Kurihara S, Ishiwata S, Fukuda N
  • Organizer: 第89回日本生理学会学術集会
  • Place of Presentation: 松本
  • Year and Date: 20120300
• [Presentation] Analyses of sarcomeric self-oscillatory properties of rat neonatal cardiomyocytes (2012)
  • Author(s): Shintani S, Yamane M, Oyama K, Kurihara S, Ishiwata S, Fukuda N
  • Organizer: Biophysical Society of USA, The 56th Annual Meeting
  • Place of Presentation: San Diego, Ca, USA
  • Year and Date: 20120200
• [Presentation] Impairment of contractility in cardiac papillary muscle with fibrosis (2012)
  • Author(s): Kusakari Y, Urashima T, Kurihara S
  • Organizer: 1st HD Physiology International Symposium: Integrative Multi-level Systems Biology for Silico Cardiology and Pharmacokinetics
  • Place of Presentation: 東京
  • Year and Date: 20120100
• [Presentation] Direct renin inhibition improved cardiac remodeling and survival in mouse model of dilated cardiomyopathy (2011)
  • Author(s): Hongo K, Morimoto S, Kusakari Y, Komukai K, Kawai M, Yoshimura M, Kurihara S
  • Organizer: Scientific Session of American Heart Association
  • Place of Presentation: Orlando FL USA
  • Year and Date: 20111100
• [Presentation] 線維化心筋における興奮収縮連関の生理学的特性 (2011)
  • Author(s): 雨宮えりか,宮坂玄樹,横田俊介,草刈洋一郎,井上天宏,浦島崇,栗原敏
  • Organizer: 第128回成医会総会
  • Place of Presentation: 東京
  • Year and Date: 20111000
• [Presentation] Unraveling the role of autonomous regulation in heartbeat: Analysis of self-oscillatory properties of rat neonatal cardiomyocytes (2011)
  • Author(s): Shintani S, Yamane M, Oyama K, Kurihara S, Ishiwata S, Fukuda N
  • Organizer: 第49回日本生物物理学会年会
  • Place of Presentation: 姫路
  • Year and Date: 20110900
• [Presentation] Real-time measurement of sarcomere length in the rodent heart by using alpha-actinin-GFP (2011)
  • Author(s): Kobirumaki F, Terui T, Mizuno A, Kagemoto T, Shimozawa T, Ishiwata S, Kurihara S, Fukuda N
  • Organizer: 第49回日本生物物理学会年会
  • Place of Presentation: 姫路
  • Year and Date: 20110900
• [Presentation] Ca^ handling impairment in papillary muscle with interstitial fibrosis (2011)
  • Author(s): Kusakari Y,Urashima T, Kurihara S
  • Organizer: 第88回日本生理学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 20110300
• [Presentation] Beta-adrenergic stimulation enhances Ca^ leak from sarcoplasmic reticulum through protein kinase A-dependent phosphorylation of ryanodine receptor under physiological condition (2010)
  • Author(s): Morimoto S, O-Uchi J, Kawai M, Kusakari Y,Komukai K,Sasaki H, Yoshimura M, Hongo K,Kurihara S
  • Organizer: Scientific Session of American Heart Association
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 20101100
• [Presentation] Changes in Ca^ handling and contraction in pressure overload-induced right ventricular hypertrophy (2010)
  • Author(s): Kusakari Y, Urashima T, Kurihara S
  • Organizer: International Academy of Cardiovascular Sciences Japan Section Meeting
  • Year and Date: 20100700
• [Presentation] Measurement of Ca^ handling in right ventricular hypertrophy induced by pressure-overload (2010)
  • Author(s): Kusakari Y, Urashima T, Kurihara S
  • Organizer: The XXth World Congress of the International Society for Heart Research
  • Place of Presentation: 京都
  • Year and Date: 20100500
• [Remarks] 東京慈恵会医科大学細胞生理学講座 HP
  • URL: http://www.jikei.ac.jp/academic/course/04_saiboseiri.html