心筋線維化における興奮収縮連関の多階層形態機能解析

• Project Area: Establishment of Integrative Multi-level Systems Biology and its Applications
• Project/Area Number: 23136515
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Jikei University School of Medicine
• Principal Investigator: 栗原 敏 東京慈恵会医科大学, 医学部, 教授 (90057026)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2012: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 線維化 / 細胞内Ca / 心筋肥大

Outline of Annual Research Achievements

病態時には心筋が線維化し収縮不全に至ることが知られている。
これまでの研究で心筋線維化に伴う興奮収縮連関に関する様々な問題が明らかにされてきた。しかし、心臓への圧負荷・伸展負荷による心筋線維化の統合的な興奮収縮連関への影響については未だ十分に明らかになっていない。
研究代表者はこれまで興奮収縮連関のメカニズム、特に細胞内Ca2+調節機構と収縮の関連について主に研究を進めてきた。本研究では心筋線維化が興奮収縮連関の各プロセスに対してどのような影響を与えているのかを調べ、最終的に心臓からの血液の拍出に対する心筋線維化の原因・影響を多階層的に解明すると共に新規治療法の創出を目的とする。
これまで右室肥大心筋を用いた一連の研究で、肥大線維化心筋を起こすグループと肥大のみで非線維化心筋グループに明確に分類できることを報告してきた。線維化を伴った肥大心筋では乳頭筋発生張力が減弱しており、介在板の消失、細胞間情報伝達蛋白であるコネキシン43の発現が減弱も認められた。一方で細胞内Caトランジェントは線維化を伴う肥大心筋では増大していることも明らかになった。生化学的検索を行ったところ、線維化を伴う肥大心筋では、非線維化肥大心筋と比べ、Ca関連蛋白のmRNA発現減少が認められた。さらに線維化を伴った肥大心筋で活動電位持続時間が著しく延長することも明らかになった。網羅的検索を目的として、DNAアレイを行ったところ、線維化を伴った肥大心筋ではFGF-23とNCAM1が非線維化心筋に比べ増大していることが明らかになった。以上のことから、肥大心筋に線維化が発生すると張力は減弱し、細胞間情報伝達機構の破綻が張力減弱の原因の一部であることが示唆された。また線維化発症のメカニズムにFGF-23とNCAM1が関与している可能性が示唆された。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

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) Issue: 2 Pages: 188-93
  • 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., Ishiwata, S., et al.
  • Journal Title: J. Biomed. Biotech. Volume: 2012 Pages: 313814-313814
  • 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) Issue: 3 Pages: 241-50
  • DOI: 10.1007/s12576-012-0203-1
  • NAID: 10030742466
  • 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., Ishiwata, S., et al
  • Journal Title: JOURNAL OF APPLIED PHYSIOLOGY Volume: 111(4) Issue: 4 Pages: 1080-1087
  • DOI: 10.1152/japplphysiol.00330.2011
  • 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., Ishiwata, S., et al
  • Journal Title: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY Volume: 301(5) Issue: 5 Pages: 1080-7
  • DOI: 10.1152/ajpcell.00161.2011
  • Peer Reviewed
• [Journal Article] Sarcomere length-dependent Ca(2+) activation in skinned rabbit psoas muscle fibers : coordinated regulation of thin filament cooperative activation and passive force (2011)
  • Author(s): Fukuda, N., Ishiwata, S., et al
  • Journal Title: JOURNAL OF PHYSIOLOGICAL SCIENCES Volume: 61(6) Issue: 6 Pages: 515-523
  • DOI: 10.1007/s12576-011-0173-8
  • NAID: 10030351129
  • Peer Reviewed
• [Journal Article] Thin filament-reconstituted skinned muscle fibers for the study of muscle physiology. (2011)
  • Author(s): Higuchi S
  • Journal Title: J Biomed Biotechnol. Volume: 2011 Issue: 1 Pages: 486021-486021
  • DOI: 10.1155/2011/486021
  • Peer Reviewed
• [Presentation] Impairment of E-C coupling in cardiac papillary muscle with fibrosis. (2013)
  • Author(s): Kusakari Y
  • Organizer: 第90回日本生理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-28
• [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
  • Organizer: 第90回日本生理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-28
• [Presentation] Real-time imaging of single sorcomeres in th mouse heart in vivo. (2013)
  • Author(s): Kobirumaki-Shimozawa F
  • Organizer: 第90回日本生理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-27
• [Presentation] Selective Modulation of SERCA Did Not Affect Ca2+ Leak from Sarcoplasmic Reticulum in Transgenic Mouse Models. (2012)
  • Author(s): Morimoto S
  • Organizer: American Heart Association 2012 Scientific session
  • Place of Presentation: Los Angeles, CA, USA
  • Year and Date: 2012-11-05
• [Presentation] Estimation of E-C coupling in cardiac papillary muscle with fibrosis. (2012)
  • Author(s): Kusakari Y
  • Organizer: The 29th Annual Meeting of the International Society for Heart Research Japanese Section.
  • Place of Presentation: 福岡
  • Year and Date: 2012-10-26
• [Presentation] Auto-oscillation (SPOC) properties of sarcomeres in rat neonatal cardiomyocytes. (2012)
  • Author(s): Shintani S
  • Organizer: 第50回日本生物物理学会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-23
• [Presentation] 心筋線維化における興奮収縮連関 (2012)
  • Author(s): 草刈洋一郎
  • Organizer: 第16回日本適応医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2012-06-08
• [Presentation] ANALYSES OF SARCOMERIC SELF-OSCILLATORY PROPERTIES OF RAT NEONATAL CARDIOMYOCYTES. (2012)
  • Author(s): Shintani S
  • Organizer: Biophysical Society of USA, The 56th Annual Meeting
  • Place of Presentation: San Diego, Ca, USA.
• [Presentation] Unraveling the role of autonomous regulation in heartbeat: Analysis of self-oscillatory properties of rat neonatal cardiomyocytes.
  • Author(s): Shintani S
  • Organizer: 第49回 日本生物物理学会年会
  • Place of Presentation: 姫路
• [Presentation] Real-time measurement of sarcomere length in the rodent heart by using alpha-actinin-GFP.
  • Author(s): Kobirumaki F
  • Organizer: 第49回 日本生物物理学会年会
  • Place of Presentation: 姫路
• [Presentation] 線維化心筋における興奮収縮連関の生理学的特性
  • Author(s): 雨宮えりか
  • Organizer: 第128回 成医会総会
  • Place of Presentation: 東京
• [Presentation] Direct Renin Inhibition Improved Cardiac Remodeling and Survival in Mouse Model of Dilated Cardiomyopathy.
  • Author(s): Hongo K
  • Organizer: American Heart Association 2011 Scientific sessions
  • Place of Presentation: Orland, FL, USA
• [Presentation] Impairment of contractility in cardiac papillary muscle with fibrosis.
  • Author(s): Yoichiro KUSAKARI
  • Organizer: 1st HD Physiology International Symposium
  • Place of Presentation: 東京
• [Presentation] Compensatory Increase in the Ca2+ Transient Is Important for Contractile Recovery of Dilated Cardiomyopathy in Mice.
  • Author(s): Hongo K
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
• [Presentation] Impairment of E-C coupling in cardiac papillary muscle with fibrosis induced by pressure overload.
  • Author(s): Kusakari Y
  • Organizer: 第89回日本生理学会学術集会
  • Place of Presentation: 松本
• [Presentation] Depressed length-dependent activation in skinned left ventricular muscles from a mouse model of dilated cardiomyopathy.
  • Author(s): Inoue T
  • Organizer: 第89回日本生理学会学術集会
  • Place of Presentation: 松本
• [Presentation] Properties of sarcomeric self-oscillations in rat neonatal cardiomyocytes : Relationship with heart beats by responce of electrical stimuli.
  • Author(s): Shintani S
  • Organizer: 第89回日本生理学会学術集会
  • Place of Presentation: 松本