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Cardiac stress-responsive mechanism and its theraprutic application

Research Project

Project/Area Number 11307013
Research Category

Grant-in-Aid for Scientific Research (A).

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

Principal Investigator

HORI Masatsugu  Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (20124779)

Co-Investigator(Kenkyū-buntansha) MASUYAMA Tohru  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70273670)
SATO Hideyuki  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70167435)
KUZUYA Tsunehiko  Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (80150340)
SATO Hiroshi  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (10294092)
KITAKAZE Masafumi  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (20294069)
西田 昌司  大阪大学, 医学系研究科, 助手 (40283783)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2000: ¥9,000,000 (Direct Cost: ¥9,000,000)
KeywordsPreconditioning / heart failure / oxygen radical / MAPK / ect0-5'-nucleotidase / Mn-SOD / S6 kinase / S6 kinsase / 心筋保護 / プレコンディショニング / アデノシン / カリウムチャネル / カルシウム拮抗薬
Research Abstract

In response to ischemic stress, oxygen radical has been found to be a key mediator, which subsequently induces anti-oxidant effectors such as adenosine, as well as Mn-SOD.This process should explain how ischemic preconditioning is beneficial for the protection against ischemic stress. We aimed to determine how the exogenous stress induces the protective effects in the heart.
(1) Mechanism of stress resistance induced in the cardiac myocytes.
We used rat cardiac myocytes, endothelial cells and smooth muscle cells as cell model, and treated them with ischemia-reperfusion, heat schock and stretch stress. After treatment, we examined effector molecule such as ecto-5'-nucleatidase and Mn-SOD by measuring their protein expression and activities. Both protein and activities of these molecules were increased. When cardiac cells were overexpressed with each of these molecules, cells over-expressing molecule showed resistance against various stresses.
(2) Intracellular signaling pathways in the cardiac cells in response to stresses.
Oxygen radicals, proposed to be a major mechanism in stress-response, was measured by using fluorescence assay system, and found to be increased in the cytosol after various types of stresses. By the biochemical analysis of intracellular signal molecules, PK-C, MAPK, JNK, P38, and S6 kinase, we found that JNK, P38, and S6 kinase are important for the induction of stress-response signaling. Thus, the final effector such as Mn-SOD should be increased by these molecules.
In conclusion, we determined the intracellular signaling pathway involved in the stress-response. P38 and S6 kinase were identified to be key mediators in this process.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Masafumi Kitakaze: "Improvement by 5-Amino-4-imidazole carboxamide riboside of the contractile dysfunction that follows brief periods of ischemia through increases in ecto-5'-nucleotidase activity and adenosine release in canine hearts"Japanese Circulation. 63. 542-553 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masafumi Kitakaze: "Role of K_<ATP> channels in cardioprotection"Current Topics in Membranes. 46. 435-448 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shiro Hoshida: "Differential effects of long-term renin-angiotensin system blockade on limitation of infarct size in cholesterol-fed rabbits."Atherosclerosis. 149. 287-294 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masafumi Kitakaze: "Nifedioine-induced coronary vasodilation in ischemic hearts is attrible to bradykinin and NO-dependent mechanisms in dogs."Circulation. 101. 311-317 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tetsuo Minamino: "Chronic Treatment with FK506 Increase p70 S6 Kinase Activity associated with Reduced Nitric Oxide Sybthase Activity in Rabbit Hearts"Cardiovascular Drugs and Therapy. 14. 329-336 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tetsuo Minamino: "Inhibition of Nitric Oxide Synthesis Induces Coronary Vascular Remodeling and Cardiac Hypertrophy Associated with the Activation of p70 S6 Kinase in Rats."Cardiovascular Drugs and Therapy. 14. 533-542 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kitakaze M, Takashima S, Minamino T, Node K, Shinozaki Y, Mori H, Kuzuya T, Hori M: "Improvement by 5-Amino-4-imidazole carboxamide riboside of the contractile dysfunction that follows brief periods of ischemia through increases in ecto-5'-nucleotidase activity and adenosine release in canine hearts."Japanese Circulation Journal. 63. 542-553 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kitakaze M, Sakata Y, Kodama K, Kuzuya T, Hori M: "Role of K_<ATP> channels in cardioprotection"Current Topics in Membranes. 46. 435-448 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hoshida S, Yamashita N, Kuzuya T, Hori M: "Differential effects of long-term renin-angiotensin system blockade on limitation of infarct size in cholesterol-fed rabbits."Atherosclerosis. 149. 287-294 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 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: "Nifedioine-induced coronary vasodilation in ischemic hearts is attrible 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
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Minamino T, Kitakaze M, Ueda Y, Asanuma H, Papst P.J, Kuzuya T, Terada N, Hori M: "Chronic Treatment with FK506 Increase p70 S6 Kinase Activity associated with Reduced Nitric Oxide Sybthase Activity in Rabbit Hearts"Cardiovascular Drugs and Therapy. 14. 329-336 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Minamino T, Kitakaze M, Papst P.J, Ueda Y, Sakata Y, Asanuma H, Ogai A, Kuzuya T, Terada N, Hori M: "Inhibition of Nitric Oxide Synthesis Induces Coronary Vascular Remodeling and Cardiac Hypertrophy Associated with the Activation of p70 S6 Kinase in Rats."Cardiovascular Drugs and Therapy. 14. 533-542 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masafumi Kitakaze: "Improvement by 5-Amino-4-imidazole carboxamide riboside of the contractile dysfunction that follows brief periods of ischemiathrough increases inecto-5'-nucleotidase activity and adenosinerelease in canine hearts."Japanese Circulation. 63. 542-553 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masufumi Kitakaze: "Role of K_<ATP> channels in cardioprotection"Current Topics in Membranes. 46. 435-448 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shiro Hoshida: "Differential effects of long-term renin-angiotensin system blockade on limitation of infarct size in cholesterol-fed rabbits."Atherosclerosis. 149. 287-294 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masafumi Kitakaze: "Nifedioine-induced coronary vasodilation in ischemic hearts is attrible to bradykinin and NO-dependent mechanisms in dogs."Circulation. 101. 311-317 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tetsuo Minamino: "Chronic Treatment with FK506 Increase p70 S6 Kinase Activity associated with Reduced Nitric Oxide Sybthase Activity in Rabbit Hearts"Cardiovascular Drugs and Therapy. 14. 329-336 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tetsuo Minamino: "Inhibition of Nitric Oxide Synthesis Induces Coronary Vascular Remodeling and Cardiac Hypertrophy Associated with the Activation of p70 S6 Kinase in Rats."Cardiovascular Drugs and Therapy. 14. 533-542 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kitakaze M et al.: "Intracoronary administration of adenosine triphosphate increases coronary blood flow and attenuates the severity of myocardial ischemic injury in dogs"Cardiovasc Drugs Ther. 13. 407-414 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitakaze M et al.: "A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependentmechanisms in dogs"J Am Coll Cardiol. 33. 242-249 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitakaze M et al.: "Adenosine and cardioprotection in the diseased heart"Jpn Circ J. 63. 231-243 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitakaze M et al.: "Improvement by 5-amino-4imidazole carboxamide riboside of the contractile dysfunction that followa brief periods of ischemia through increases in ecto-5-…"Jpn Circ J. 63. 542-553 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ito H et al.: "Intravenous nicorandil can preserve microvascular integrity and myocardial viabillity in patients with reperfused anterior wall myocardial infarcition"J Am Coll Cardiol. 33. 654-660 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Inoue K, Minamino T et al.: "Antecedent angina pectoris as a predictor of better functional and clinical outocomes in patients with an inferior wall acute myocardial infarction"Am J Cardiol. 83. 159-163 (1999)

    • Related Report
      1999 Annual Research Report

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

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