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心筋細胞の刺激受容機構とシグナル伝達系

Research Project

Project/Area Number 06274101
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

矢崎 義雄  東京大学, 医学部・附属病院, 教授 (20101090)

Co-Investigator(Kenkyū-buntansha) 寒川 賢治  国立循環器病センター, 生化学部, 部長 (00112417)
堀 正二  大阪大学, 医学部附属病院, 講師 (20124779)
高井 義美  大阪大学, 医学部, 教授 (60093514)
横山 光宏  神戸大学, 医学部附属病院, 教授 (40135794)
篠山 重威  京都大学, 医学部附属病院, 教授 (70109007)
Project Period (FY) 1994 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥117,000,000 (Direct Cost: ¥117,000,000)
Fiscal Year 1996: ¥35,000,000 (Direct Cost: ¥35,000,000)
Fiscal Year 1995: ¥40,000,000 (Direct Cost: ¥40,000,000)
Fiscal Year 1994: ¥42,000,000 (Direct Cost: ¥42,000,000)
Keywordscardiomyocytes / mechanical stress / signal transduction / calcium ion / adrenomedulin / endothelin / Angiotensin II / G protein / 細胞内情報伝達 / エンドセリン / アンジオテンシンII / アドレノメデュリン / 心不全 / 心肥大 / ANP / BNP
Research Abstract

機械的刺激により心筋細胞内において蛋白質リン酸化のカスケードが活性化され、特異的な遺伝子発現や蛋白合成の亢進がおこり、心肥大が形成されることをin vitroで心筋細胞を進展させることにより示した。心筋細胞より分泌されるアンジオテンシンIIやエンドセリンといった血管収縮物質が重要な役割を果たしていること、しかしアンジオテンシンIIのシグナルの存在しないマウス(アンジオテンシンII1型受容体ノックアウトマウス)においても機械的刺激によりコントロールマウスよりも強い肥大時反応が生ずることも示した。このことは、機械的刺激それ自身ないしは未知の物質が心肥大形成に重要であることを示している。ラット血小板中のcAMP活性の増加を指標としてヒト褐色細胞腫組織より発見されたアドレノメデュリン及びその前駆体よりできる20残基のペプチドであるPAMPは、全く新しい降圧ペプチドである。アドレノメデュリンは、副腎以外にも肺・心臓・腎臓など広範囲で発現しており、敗血症性ショックなど種々の循環器疾患で血中濃度が上昇していたことより、循環調節に深く関与していると考えられた。インスリン受容体様チロシンキナーゼであるLTKをトランスジェニックマウスを用いて過剰発現させたところ、心肥大、心筋線維の錯綜配列、心筋細胞のアポトーシスが認められた。心臓の線維化や炎症細胞の浸潤は軽度であった。このトランスジェニックマウスの心臓において、心房性ナトリウム利尿ペプチド、β型ミオシン重鎖、骨格筋型アクチンなどの胎児型蛋白の発現が認められた。この心臓において、MAPキナーゼの内でERK活性は変わらなかったが、JNK、p38MAPKの活性がトランスジェニックマウスにおいて高値であった。JNK、p38MAPKはアポトーシスに関係するという報告があることから、このJNK、p38MAPK活性の亢進がアポトーシスの誘導に関係している可能性が考えられた。

Report

(3 results)
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Komuro I.,Kudo S.et al: "Mechanical stretch activates the stress-activated protein kinasas in cardiac myocytes." FASEB J.10(5). 631-636 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamazaki T.,Komuro I.et al: "Endothelin-1 is Involved in Mechanical stress-induced Cardiomyocyte Hypertrophy" J.Biol Chem. 271(6). 3221-3228 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shiojima I.,Komuro I. et al: "Molecular Cloning and Characterization of Human Cardiac Homeobox Gene CSX1" Circ Res. 79(5). 920-929 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Zou Y.,Komuro I.et al: "Protein Kinase C,but Not Tyrosine Kinases or Ras.Plays a Critical Role in Angiotensin II-induced Activation of Rof-1 Kinase and Extracellular Signal Protein Kinases in Cardiac Myocytes." J Biol Chem. 271(52). 33592-33597 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamazaki T.,Komuro I.et al: "Molecular aspects of mechanical stress induced cardiac hypertrophy." Mol Cell Biochem. 163/164. 197-201 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kudoh S., Komuro I.et al: "Angiotensin II stimulates C-Jun NH_2-Terminal Kinase in Cultured Cardiac Myocytes of Neonatal Rats" Circ Res. 80(1). 139-146 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Komuro I.,Izumo S.: "Cardiac-specific homeobox-containing gene of. the mouse in “Developmental"mechanisms of heart disease"." Markwald RR.,Clark E.B.,Takao A.Futura N.Y., 679 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Komuro I.,Shiojima I.,Izumo S.et al: "Human and murine cardiac-specific homeobox-containing genes.in“Cardiac Development and Gene Regulation"." Yazaki Y.Excerpta Medica.Ltd.Tokyo, 153 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Komuro I,Yazaki Y.: "Intracelular signaling puthways in cauthec myccytesinduced by mechanical stress." Trends in Card Med. 4(3). 117-121 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yamazaki T.Komuro I.etal.: "Mechanical stress activatesprotein kinase cascoade of phesplorylation in necnatal rat caradiac myocytes" J Clin Invest. 96(1). 438-446 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kihara Y,InokoM,Sasayama S.: "L-Methionine augments myaardial contraction by sensitizing myofilament for calcium" Circ Res. 77. 80-87 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Miki N,Hamanori Y,Hirata K,etal.: "Transforming Growth Factor-βl Potentiated αi-adrergiv and stretch-induced C-fos mRNA expressioninratmyacabtia ceils" Circ Res. 175. 8-14 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takaishi,KikudhiA.et.al.: "Invoivement of the irribitcry DP/GTP exchange Protein (rhc GDI)incell motility." Mol Cell Biol. 13. 72-79 (1993)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nishiyama T,Sasaki T.et.al.: "Racpel is inbeolved in iasulin-inducrldmembrabrare pifflinaandrhop21 is inceivedin hepatpcyte yrowthtactor and 12-0-retradecancylphorbol-13-cete(TPA)-inducea membrane ruffing in inKBcells" Mol Cell Biol. 14. 2447-2456 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shiojima I,Yamazaki T,Komuro I.: "Malecalaraspects of mecdhenical stress-induced cardiachypeoetrecphyoncltaikire un “New henzans for failing heaet syndrome"" Sasayama S.Spniger-Verlag,Tokyo, 430 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shiojima I,Yamazaki T,Komuro I.: "Malecularaspects of the control mydaroin relaxoticp in Diastolicrelaxation" Grossman W,Lerell BH.Kluwer Academic Publishers Bcston, 348 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] M.Kojima,Y.Yazaki et.al: "Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and in hibits the intracellular-signaling pathway of strech-mediated cardionyocyie hypetiophy in vitro" Circulation. 89(5). 2204-2211 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Kihara,S.Sasayama et.al: "Sodium/calcium exchange modulates intracellular calcium overload during posthypoxic reoxygenation in mummalian working myocardium" Journal of Clinical Investion. 93. 1275-1284 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nishiyama,T.Takai,Y.et.al: "Rac p21 is involved in insulin-induced memprane ruffling and rho p21 is involvod in hepatoilx growth factor-and 12-O-telradecanoylp norbol-13-acetate(TPA)-induced memorme ruffling in KB cells" Molecular cell Biology. 14. 2447-2456 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] N.Miki,M.Yokoyama et.al: "Transforming Growth Factor-B1 Potentiated α-1 Adrenergic and Stretch-Induced c-fos mRNA Expression in Rat Myocardial Cells" Circulation Research. 75(1). 8-14 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hori,M.et.al.: "β-adrenergic stimulation disassembles microtubules in neonatal rat cultured cardiomyocytes through intracellular Ca^<2+> overload" Circulation Research. 75. 324-334 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ito H.et.al: "Endothelih ETA receptar antagonist blocks cardiac hypertrophy prouoked by hemodynamic overload," Circulation. 89. 2198-2203 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] I.Shiojima et.al.: "Diastolic Relaxation of the Heart" Kluwer Academic Publishers,Boston, 348 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2017-10-10  

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