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Acquirement of the Ischemic Cardioprotection and ecto-5'-nucleotidase : Investigation of the Receptor Activation and Subsequent Signal Transduction

Research Project

Project/Area Number 12470153
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionOsaka University

Principal Investigator

MASUYAMA Tohru (2001)  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70273670)

北風 政史 (2000)  大阪大学, 医学系研究科, 助手 (20294069)

Co-Investigator(Kenkyū-buntansha) KUZUYA Tsunehiko  Osaka Shoin Women's University, Faculty of Human Life and Science, Professor, 学芸学部, 教授 (80150340)
TADA Michihiko  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (90093434)
HORI Masatsugu  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20124779)
TAKASHIMA Seiji  Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
SATO Hideyuki  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70167435)
宮崎 純一  大阪大学, 医学系研究科, 教授 (10200156)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2001: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2000: ¥10,200,000 (Direct Cost: ¥10,200,000)
KeywordsAdenosine / ecto-5'-nucleotidase / PKC / KATP Channels / P70S6 Kinase / P38 MAP Kinase / Preconditioning / 心筋梗塞 / 心不全 / cDNAマイクロアレイ / 遺伝子発現 / 多施設臨床試験 / KATPチャネル開口剤
Research Abstract

We had completed in preparing the ecto-5'-nucleotidase overexpression mice. The infarct size in the in vivo model afforded by 30-min ischemia and 2-hour reperfusion was significantly smaller (24 %) than that in the control (49 %). The ecto-5'-nucleotidase was rapidly activated early in the ischemic phase, which resulted in the increase in adenosine production. We also examined using these mice the changes in mRNA expression pattern by micro-array system, which revealed that adenosine in the ischemic phase plays cardioprotective roles.
In healthy beagle dog model, ischemic preconditioning caused marked reduction in infarct size afforded by 90-min ischemia and 6-hour reperfusion, which was blunted by 1)PKC inhibition, 2) ecto-5'-nucleotidase inhibition, 3)adenosine A1 receptor blockade and 4)p38MAPK inhibition during preconditioning period, or partially attenuated by either sarcolemmal or mitochondrial KATP channel blockade. Furthermore, p70S6 kinase inhibition abolished the second-window … More protection after 48 hours of the preconditioning ischemia. These data indicate that the immediate and second-window preconditioning protect myocardium by different mechanisms.
Now we are establishing the cDNA micro-array system in dogs, which can analyze the changes in as much as 10000 mRNA expression patterns at once. On this process, we prepared a pilot system that can analyze 100 known mRNA at once. Using this system, we tested the effect of 3-hour low flow ischemia on the 100 mRNA expression patterns and found that about 15 kinds of mRNA among them showed significant changes.
In clinical settings, we are now operating some open or double-blind randomized case-control multi-center trials to examine the effect of an ATP derivative, a KATP channel opener, and a human hAMP derivative on acute myocardial infarction (COAT and J-WIND studies) and the effect of dipyridamol on stable mild chronic heart failure (ROAD study), under the approval of the ethical committee. COAT study now revealed that the acute phase treatment with ATP derivative resulted in better outcome 1-year later. Interestingly, ROAD study now showed that the chronic treatment with dipyridamol resulted in the increase in ADL, reduction in plasma BNP and aldosterone levels. These studies are now going on further toward the final results. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Sanada, Kitakaze, Takashima, Hori et al.: "Role of the Mitochondrial and Sarcolemmal KATP Channels in Ischemic Preconditioning on the Canine Heart"Am J Physiol Heart Circ Physiol. 280・1. H256-H263 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sanada, Kitakaze, Takashima, Kuzuya, Hori et al.: "Role of Phasic Dynamism of P38 Mitogen-activated Protein Kinase Activation in the Ischemic Preconditioning on the Canine Heart"Circ Res.. 88・2. 175-180 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sanada, Kitakaze, Takashima, Kuzuya, Hori et al.: "Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase-III Inhibitors"Circulation.. 104・6. 705-710 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kitakaze, Takashima, Sanada, Hori et al.: "Role of cellular acidosis in production of nitric oxide in canine ischemic myocardium"J Mol Cell Cardiol.. 33・9. 1727-1737 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Asanuma, Kitakaze, Takashima, Sanada, Hori et al.: "Nifedipine limits infarct size via NO-dependent mechanisms in dogs"Basic Res Cardiol.. 96・5. 497-505 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Asakura, Kitakaze, Takashima, Sanada, Hori et al.: "Adenosine-induced cardiac gene expression of ischemic murine hearts revealed by cDNA Array Hybridization"Jpn Circ J.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kitakaze M, Asanuma H, Takashima S, Minamino T, Ueda Y, Sakata Y, Asakura M, Sanada S, Kuzuya T, Hori M.: "Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to bradykinin- and NO-dependent mechanisms in dogs"Circulation. 101. 311-7 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kitakaze M, Node K, Asanuma H, Takashima S, Sakata Y, Asakura M, Sanada S, Shinozaki Y, Mori H, Kuzuya T, Hori M.: "Protein Tyrosine Kinase Is Not Involved in the Infarct Size Limiting Effect of Ischemic Preconditioning in Canine Hearts"Circ Res.. 87. 303-8 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sanada S, Kitakaze M, Asanuma H, Harada K, Ogita H, Node K, Takashima S, Sakata Y, Asakura M, Shinozaki Y, Mori H, Kuzuya T, Hori M.: "Role of the Mitochondrial and Sarcolemmal KATP Channels in Ischemic Preconditioning on the Canine Heart"Am J Physiol Heart Circ Physiol. 280. H256-63 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sanada S, Kitakaze M, Papst PJ, Hatanaka K, Asanuma H, Aki T, Shinozaki Y, Ogita H, Node K, Takashima S, Asakura M, Kuzuya T, Mori H, Terada N, Yoshida Ki, Hori M.: "Role of Phasic Dynamism of P38 Mitogen-activated Protein Kinase Activation in the Ischemic Preconditioning on the Canine Heart"Circ Res. 88. 175-80 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sanada S, Kitakaze M, Asanuma H, Papst PJ, Node K, Liao Y, Shinozaki Y, Ogita H, Takashima S, Sakata Y, Asakura M, Kuzuya T, Terada N, Mori H, Hori M.: "Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase-III Inhibitors. -The Role of Protein Kinase A and P38 Mitogen-activated Protein Kinase-"Circulation. 104. 705-10 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Asanuma H, Kitakaze M, Funaya H, Takashima S, Minamino T, Node K, Sakata Y, Asakura M, Sanada S, Shinozaki Y, Mori H, Kuzuya T, Hori M.: "Nifedipine Limits Infarct Size via NO-dependent Mechanisms In Dogs"Basic Res Cardiol. 96. 497-505 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kitakaze M, Asakura M, Sakata Y, Asanuma H, Sanada S, Kuzuya T, Miyazaki J, Takashima S, Hori M.: "cDNA Array Hybridization Reveals Cardiac Gene Expression in Acute Ischemic Murine Hearts"Cardiovasc Drugs Ther.. 15. 125-30 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Asanuma H, Kitakaze M, Node K, Takashima S, Sakata Y, Asakura M, Sanada S, Shinozaki Y, Mori H, Tada M, Kuzuya T, Hori M.: "Benidipine, a Long-acting Ca Channel Blocker, Limits Infarct Size via NO-dependent Mechanisms In Dogs"Cardiovasc Drugs Ther.. 15. 225-31 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sanada, Kitakaze, Takashima, Hori et al.: "Role of the Mitochondrial and Sarcolemmal KATP Channels in Ischemic Preconditioning on the Canine Heart"Am J Physiol Heart Circ Physiol.. 280・1. H256-H263 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sanada, Kitakaze, Takashima, Kuzuya, Hori et al.: "Role of Phasic Dynamism of P38 Mitogen-activated Protein Kinase Activation in the Ischemic Preconditioning on the Canine Heart"Circ Res.. 88・2. 175-180 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sanada, Kitakaze, Takashima, Kuzuya, Hori et al.: "Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase-III Inhibitors"Circulation.. 104・6. 705-710 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kitakaze, Takashima, Sanada, Hori et al.: "Role of cellular acidosis in production of nitric oxide in canine ischemic myocardium"J Mol Cell Cardiol.. 33・9. 1727-1737 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Asanuma, Kitakaze, Takashima, Sanada. Hori et al.: "Nifedipine limits infarct size via NO-dependent mechanisms in dogs"Basic Res Cardiol.. 96・5. 497-505 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Asakura, Kitakaze, Takashima, Sanada, Hori et al.: "Adenosine-induced cardiac gene expression of ischemic murine hearts revealed by cDNA Array Hybridization"(in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Sanada,Kitakaze,Takashima,Kuzuya,Hori, et al.: "Role of Phasic Dynamism of P38 Mitogen-activated Protein Kinase Activation in Ischemic Preconditioning of the Canine Heart."Circ Res.. 88・2. 175-80 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sanada,Kitakaze,Takashima,Kuzuya,Hori, et al.: "Role of mitochondrial and sarcolemmal K(ATP) channels in ischemic proconditioning of the canine heart."Am J Physiol Heart Circ Physiol.. 280・1. H256-63 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Minamino,Kitakaze,Kuzuya,Hori, et al.: "Inhibition of nitric oxide synthesis induces coronary vascular remodeling and cardiac hypertrophy associated with the activation of p70 S6 kinase ..."Cardiovasc Drugs Ther.. 14・5. 533-42 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kitakaze,Hori.: "Adenosine therapy : a new approach to chronic heart failure."Expert Opin Investig Drugs.. 9・11. 2519-35 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kitakazo,Takashima,Kuzuya,Hori, et al.: "Protoin tyrosine kinase is not involved in the infarct size-limiting effect of ischemic preconditioning in canine hearts."Circ Res.. 87・4. 303-8 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Node,Kitakaze,Kuzuya,Hori, et al.: "Increased cardiac levels of nitric oxide in patients with chronic heart failure."Am J Cardiol.. 86・4. 474-7 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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