The Identification of Cardioprotective Mechanism Afforded by Ischemic Preconditioning and its Application to the Therapy Against Acute Myocardial Infarction

• Project/Area Number: 13470147
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka University
• Principal Investigator: SATO Hiroshi (2002) Osaka University, Graduate School of Medicine, Assistant Prof., 医学系研究科, 助手 (10294092); 佐藤 秀幸 (2001) 大阪大学, 医学系研究科, 助手 (70167435)
• Co-Investigator(Kenkyū-buntansha): KUZUYA Tsunehiko Osaka Shoin Womens' College, Professor., 学芸学部, 教授 (80150340) ; HORI Masatsugu Osaka University, Graduate School of Medicine, Professor., 医学系研究科, 教授 (20124779) ; KITAKAZE Masafumi National Cardiovascular Center, Division of Physiological Examination, Director., 生理機能検査部, 部長(研究職) (20294069) ; MIYAZAKI Jun-ichi Osaka University, Graduate School of Medicine, Professor., 医学系研究科, 教授 (10200156) ; TAKEDA Hiroshi Osaka University, Graduate School of Medicine, Professor., 医学系研究科, 教授 (20127252)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥14,600,000 (Direct Cost: ¥14,600,000); Fiscal Year 2002: ¥4,600,000 (Direct Cost: ¥4,600,000); Fiscal Year 2001: ¥10,000,000 (Direct Cost: ¥10,000,000)
• Keywords: PKC / ecto-5'-nucleotidase / PKA / KATP Channels / P70S6 Kinase / P38 MAP Kinase / Preconditioning / J-WIND / アデノシン / 一酸化窒素(NO) / Rhoキナーゼ / プロテインキナーゼC / プロテインキナーゼA / J-WIND試験 / 心保護作用 / 心筋梗塞 / p38MAPキナーゼ / HSP27 / 多施設臨床試験 / KATPチャネル開口剤

Research Abstract

1. We have successfully developed the transgenic mice overexpressing the adenosine producing enzyme (ecto-5'-nucleotidase). Examination of these mice with cardiac ischemia and reperfusion resulted in smaller infarct size than that of control group. This effect was completely abolished by the adenosine receptor antagonist (8-SPT). The microarray analysis of the ischemic control myocardium in vivo showed the 230positive clones of m-RNA, including that of ecto-5'-nucleotidase in upper grade. These results show that adenosine is an endogenous cardioprotective agent and the exogenous treatment with adenosine could be a cardioprotective strategy.
2. In the anesthetized canine model, preconditioning procedure markedly reduced infarct size afforded by 90-minutes of ischemia and 6-hours of reperfusion. This effect was completely abolished by preischemic PKC inhibition, preischemic p38MAPK inhibition, or KATP channel blockade. Preconditioning translocated HSP27 from cytosol to membrane and myofibril that was inhibited by preischemic p38MAPK inhibition. We also found that PKA and Rho-kinase also take park in the cardioprotective mechanism of preconditioning.
3. We conducted COAT study, which examined the cardioprotective effect by superacute injection of ATP analogue. This study enrolled about 40 patients with acute myocardial infarction, and revealed the positive cardioprotective effect after 1 year. We are also conducting J-WIND study, examinating the cardioprotective effect by superacute injecti

Research Products

• [Publications] Asakura M, Kitakaze M, Sakata Y, Asanuma H, Sanada S, et al.: "Adenosine-induced cardiac gene expression of ischemic murine hearts revealed by cDNA Array Hybridization"Circ J.. 66・1. 93-96 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kitakaze M, Asanuma H, Node K, Takashima S, Sanada S, et al.: "ACE inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium : Role of bradykinin"J Am Coll Cardiol.. 40・1. 162-166 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sanada S, Node K, Takashima S, Hori M, Kitakaze M, et al.: "Opening of ATP-sensitive Potassium Channel Attenuates Cardiac Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis"J Am Coll Cardiol.. 40・3. 991-997 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ogita H, Node K, Sanada S, Mori H, Hori M, Kitakaze M. et al.: "Amelioration of Ischemia-and Reperfusion-induced Myocardial Injury by the Selective Estrogen Receptor Modulator, Raloxifene, in the Canine Heart"J Am Coll Cardiol.. 40・3. 998-1005 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Asanuma H, Node K, Sanada S, Hori M, Kitakaze M. et al.: "Celiprolol, Increases Coronary Blood Flow and Reduces the Severity of Myocardial Ischemia via Nitric Oxide Release"J Cardiovasc Pharmacol.. (In Press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sanada S, Kitakaze M.: "Cellular Mechanisms and Signal Transduction of Ischemic Preconditioning : Current Evidence, Clinical Applications and Future Direction"Curr Med Chem.. (In Press).
  • Description: 「研究成果報告書概要(和文)」より
• [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. 311-317 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [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. 303-308 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sanada S, Kitakaze M, Asanuma H, Harada K, Ogita H, Node K, Takashima S, Sakata Y, Asakura M, Shinozaki Y, Mo 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. H256-263 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [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. 175-180 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [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. 705-710 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [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
• [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. 125-130 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [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. 225-231 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Asakura M, Kitakaze M, Sakata Y, Asanuma H, Sanada S, Kim J, Ogita H, Liao Y, Node K, Takashima S, Tada M, Hori M.: "Adenosine-induced cardiac gene expression of ischemic murine hearts revealed by cDNA Array Hybridization."Circ J.. 66. 93-96 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kitakaze M, Asanuma H, Funaya H, Node K, Takashima S, Sanada S, Asakura M, Ogita H, Kim J, Hori M.: "ACE inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium: Role of bradykinin."J Am Coll Cardiol.. 40. 162-166 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ogita H, Node K, Asanuma H, Sanada S, Liao Y, Takashima S, Asakura M, Mori H, Shinozaki Y, Hori M, Kitakaze M.: "Amelioration of Ischemia- and Reperfusion-induced Myocardial Injury by the Selective Estrogen Receptor Modulat** Raloxifene, in the Canine Heart."J Am Coll Cardiol.. 40. 998-1005 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Asanuma H, Node K, Minamino T, Sanada S, Takashima S, Ueda Y, Sakata Y, Asakura M, Kim J, Ogita H, Tada M, Hori M, Kitakaze M.: "Celiprolol, Increases Coronary Blood Flow and Reduces the Severity of Myocardial Ischemia via Nitric Oxide Release."J Cardiovase Pharmacol.. (in Press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ogita H, Node K, Asanuma H, Sanada S, Takashima S, Minamino T, Soma M, Kim J, Hori M, Kitakaze M.: "Eicosapentaenoic Acid Reduces Myocardial Injury Induced by Ischemia and Reperfusion in Rabbit Hearts."J Cardiovasc Pharmacol.. (In Press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sanada S, Kitakaze M.: "Cellular Mechanisms and Signal Transduction of Ischemic Preconditioning: Current Evidence, Clinical Applications and Future Direction."Curr Med Chem.. (In Press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Asakura M, Kitakaze M, Sakata Y, Asanuma H, Sanada S, et al.: "Adenosine-induced cardiac gene expression of ischemic murine hearts revealed by cDNA Array Hybridization"Circ J.. 66・1. 93-96 (2002)
• [Publications] Kitakaze M, Asanuma H, Node K, Takashima S, Sanada S, et al.: "ACE inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium : Role of bradykinin"J Am Coll Cardiol.. 40・1. 162-166 (2002)
• [Publications] Sanada S, Node K, Takashima S, Hori M, Kitakaze M, et al.: "Opening of ATP-sensitive Potassium Channel Attenuates Cardiac Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis"J Am Coll Cardiol.. 40・3. 991-997 (2002)
• [Publications] Ogita H, Node K, Sanada S, Mori H, Hori M, Kitakaze M. et al.: "Amelioration of Ischemia-and Reperfusion-induced Myocardial Injury by the Selective Estrogen Receptor Modulator, Raloxifene, in the Canine Heart"J Am Coll Cardiol.. 40・3. 998-1005 (2002)
• [Publications] Asanuma H, Node K, Sanada S, Hori M, Kitakaze M. et al.: "Celiprolol, Increases Coronary Blood Flow and Reduces the Severity of Myocardial Ischemia via Nitric Oxide Release"J Cardiovasc Pharmacol.. (In Press).
• [Publications] Sanada S, Kitakaze M.: "Cellular Mechanisms and Signal Transduction of Ischemic Preconditioning : Current Evidence, Clinical Applications and Future Direction"Curr Med Chem.. (In Press).
• [Publications] Sanada, Kitakaze, Takashima, Horei 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)
• [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)
• [Publications] Sanada, Kitakaze, Takashima, Kuzuya, Hori et al.: "Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase-III Iinhibitors"Circulation. 104・6. 705-710 (2001)
• [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)
• [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)
• [Publications] Asanuma, Kitakaze, Takashima, Sanada, Hori et al.: "Benidipine, a long-acting Ca channel blocker, limits infarct size via bradykinin-and NO-dependent mechanisms in canine hearts"Cardiovasc Drugs Ther.. 15・3. 225-231 (2001)