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1998 Fiscal Year Final Research Report Summary

Development of Chronic Heart Failure Model Caused by Inflammatory Cytokines and Establishment of Prophylactic and Therapeutic Strategies for the Heart Failure

Research Project

Project/Area Number 08557050
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Circulatory organs internal medicine
Research InstitutionKyushu University

Principal Investigator

SHIMOKAWA Hiroaki  Kyushu Univ, Res Inst of Cardiol, Assoc Prof, 医学部, 助教授 (00235681)

Co-Investigator(Kenkyū-buntansha) 市來 俊弘  九州大学, 医学部, 助手
TSUTSUI Hiroyuki  Kyushu Univ, Res Inst of Cardiol, Assist Prof, 医学部, 講師 (70264017)
SUMIMOTO Hideki  Kyushu Univ, Dept of Mol Biol, Prof, 医学部, 教授 (30179303)
SUEISHI Katuo  Kyushu Univ, Dept of Pathol, Prof, 医学部, 教授 (70108710)
UTSUMI Hideo  Kyushu Univ, Dept of Pharmacol, Prof, 藥学部, 教授 (20101694)
Project Period (FY) 1996 – 1998
Keywordsinflammatory cytokine / adhesion molecules / nitric oxide / superoxide anion / peroxynitrite
Research Abstract

(1)We have developed a canine model of sustained myocardial dysfunction, in which interleukin-1beta (lL-1beta) bound to microspeheres (MS) was selectively injected into the left main coronary artery. This novel model is unique as the long-term effect of an inflammatory cytokine on the heart can be examined without causing its systemic effect. In this model, sustained left ventricular (LV) dysfunction was noted in animals that received IL-1beta-MS but not in those that received MS alone.
(2)First, the role of adhesion molecules was examined. When the adhesion molecule inhibitor, SLeX-oligosaccharide (SLeX-OS), or the P-selectin inhibitor, PB1.3, was pre-administered, the leukocyte infiltration and sustained LV dysfunction caused by IL-1beta were markedly inhibited, indicating the important role of adhesion molecules in this model.
(3)Second, the role of nitric oxide (NO) derived from inducible NO synthase (iNOS) was examined. When the non-specific protein synthase inhibitor, dexamethasone … More (DEX), or the iNOS inhibitor, aminoguanidine (AG), was pre-administered, the IL-beta-induced sustained myocardial dysfunction was markedly prevented, indicating the important role of iNOS-derived NO in the pathogenesis of the myocardial dysfunction in this model.
(4)Third, the role of superoxide anion was examined. When the superoxide anion synthesis inhibitor, OPC-6535, was pre-administered, the IL-1beta-induced sustained myocardial dysfunction was markedly prevented, indicating that superoxide anion may also play an important role in our model.
(5)Finally, we measured the myocardial concentrations of nitrotyrosine as a marker for peroxynitrite production as a result of the interaction between NO and superoxide anion. Superoxide anion is known to be a more cytotoxic factor than NO or superoxide anion. The results showed that nitrotyrosine formation was increased in the IL-beta group, whereas the formation was markedly inhibited in the SLeX-OS, PB 1.3, DEX, AG, and OPC-6535 groups. There was a significant correlation between he myocardial concentrations of nitrotyrosine and LV dysfunction, indicating that peroxynitrite is at least one of the major causative factors for the myocardial dysfunction in our model in vivo. Less

  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Oyama J et al.: "Role of nitric oxide and paroxynitrite in the cytokine-induced myocardial dysfunction in dogs in vivo." Journal of Clinical Investigation. 101. 2207-2214 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Momii H et al.: "Inhibition of adhesion molecules markedly ameliorates cytokine-induced sustained myocardial dysfunction in dogs in vivo." Journal of Molecularand Cellular Cardiology. 30. 2637-2650 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cheng X-S et al.: "Role of superoxide anion in the pathogenesis cytokine-induced myocardial dysfunction in dogs in vivo." Cardiovascular Research. in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shimokawa H et al.: "Cytokine generation capacities of monocytes are reducedin patients with severe heart failure." American Heart Journal. 136. 991-1002 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shimokawa H: "Acute myocardial infarction and cytokines." Journal of Immunology and Immuno-Pharmacology. 18. 30-34 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shimokawa H: "Endothelial dysfunction in hypertension." Journal of Atherosclerosis and Thombosis. 4. 118-127 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tashiro H,Shimokawa H et al.: "Altered plasma levels of cytokines in patients with ischemic heart disease." Coronary Artery Disease. 8. 143-147 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fukumoto Y,Shimokawa H,et al.: "Vasculoprotective role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1 β in pigs in vivo." Circulation. 96. 3104-3111 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Katsumata N,Shimokawa H,et al.: "Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1 β." Circulation. 96. 4357-4363 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shimokawa H,et al.: "Chronic treatment with interleukin-1 β induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derivedgrowth factor." Journal of Clinical Investigation. 97. 769-776 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyama J,Shimokawa H,Momii H,et al.: "Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dys-function in dogs in vivo." Journal of Clinical Investigation.101. 2207-2214 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Momii H,Shimokawa H,Oyama J,et al.: "inhibition of adhesion molecules markedly ameliorates cytokine-induced sustained myocardial dysfunction in dogs in vivo." Journal of Molecular and Cellular Cardiology.30. 2637-2650 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cheng XS,Shimokawa H,Momii H,et al.: "Role of superoxide anion in thepathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo." Cardiovascular Research.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shimokawa H,Kuroiwa M,Takeshita A: "Cytokine generation capacities of monocytes are reduced in patients with severe heart failure." American Heart Journal.136. 991-1002 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shimokawa H: "Acute myocardial infarction and cytokines." Journal of Immunology and Immuno-Pharmacology.18. 30-34 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shimokawa H: "Endothelial dysfunction in hypertension." Journal of Atherosclerosis and Thrombosis.4. 118-127 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tashiro H,Shimokawa H,et al.: "Altered plasma levels of cytokines in patients with ischemic heart disease." Coronary Artery Disease.8. 143-147 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fukumoto Y,Shimokawa H,et al.: "Vasculoprotective role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1beta in pigs in vivo." Circulation.96. 3104-3111 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Katsumata N,Shimokawa H,et al.: "Enhanced myosin light chain phosphory-lations as a central mechanism for coronary artery spasm in a swine model with inter-leukin-1beta." Circulation.96. 4357-4363 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shimokawa H,et al.: "Chronic treatment with interleukin-1beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor." Journal of Clinical Investigation.97. 769-776 (1996)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08   Modified: 2017-10-11  

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