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2001 Fiscal Year Final Research Report Summary

MOLECULAR MECHANISMS OF CARDIOVASCULAR REMODELING INDUCED BY CHRONIC INHIBITION OF NITRIC OXIDE SYNTHESIS : ROLE OF NF-_B AND MCP-1

Research Project

Project/Area Number 11470164
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

EGASHIRA Kensuke  Kyushu Univ, Dept of Cardiovasc Med, Associate Prof., 医学部・附属病院, 講師 (60260379)

Co-Investigator(Kenkyū-buntansha) ICHIKI Toshihiro  Kyushu Univ, Dept of Cardiovasc Med, Prof., 医学部・附属病院, 助手 (80311843)
UTSUMI Hideo  Kyushu Univ, Dept of Pharmacy, Assist Prof., 大学院・薬学研究院, 教授 (20101694)
SUEISHI Katuo  Kyushu Univ, Dept of Cardiovasc Med, Prof., 大学院・医学研究院, 教授 (70108710)
NAKAYAMA Kei-ichi  Kyushu Univ, Dept of Med, Prof., 大学院・医学研究院, 教授 (80291508)
Project Period (FY) 1999 – 2001
Keywordsgene transfer / nitric oxide / NF-κB / MCP-1 / arteriosclerosis / inflammation / fibrosis
Research Abstract

Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of N^ω-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation [monocytes infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, and nuclear factor-kB (NF-_B) activation] in the early phase (day 3) and subsequent arteriosclerotic changes (medial thickening and perivascular fibrosis) in the late phase (day 28). MCP-1 is presumed to be a potent chemotactic factor for monocytes. NF-_B is an oxidative stress-sensitive transcription factor that regulates transcription of inflammation-promoting genes including MCP-1. However, no direct evidence for the role of NF-_B and MCP-1 in the development of such cardiovascular remodeling has been addressed in this model with chronic inhibition of NO synthesis. In the first experimental protocol, we examined the effect of in vivo transfection of cis element decoy against NF-_B to the heart. The transfection of NF-_B decoy prevented the L-NAME-induced increase in NF-_B activity, vascular inflammation and MCP-1 expression. In the second protocol, we investigated the effect of the neutralizing anti-MCP-1 antibody. Treatment with the anti-MCP-1 antibody prevented the L-NAME-induced early inflammatory changes and thus normalized coronary vascular medial thickening in the late phase. In contrast, neither NF-κB decoy transfection nor the antibody reduce the development of perivascular fibrosis, the gene expression of TGF_1, or systolic pressure overload induced by L-NAME. These results suggest that endothelium-derived NO decreases MCP-1 by suppressing oxidative stress-sensitive transcription factors such as NF-_B. The present study may provide a new aspect of how endothelium-derived NO contributes to anti-inflammatory and anti-arteriosclerotic properties of the vascular endothelium in vivo.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Ni WH, Egashira K, et al.: "New Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Inhibits Atherosclerosis in ApoE-knockout Mice"Circulation. 103. 2096-2101 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ni WH, Egashira K, et al.: "Anti-inflammatory and Anti-arteriosclerotic Actions of HMG-CoA Reductase Inhibitors in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis"Circulation Research. 189. 415-421 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakamura R, Egashira K, et al.: "Increased Inactivation of Nitric Oxide is Involved in Impaired Coronary Flow Reserve in Dogs with Tachycardia-Induced Heart Failure"Am J Physiol. 281. H2619-H2625 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kataoka C, Egashira K, et al.: "Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats"Hypertension. (印刷中). (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Zhao Q, Egashira K, et al.: "Vascular Endothelial Growth Factor is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis"(2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Usui M, Egashira K, et al.: "Pathogenic role of oxidative stress in vascular angiotensin-converting enzyme activation in long-term blockade of nitric oxide synthesis in rats"Hypertension. 34. 546-551 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Usui M, Egashira K, et al.: "Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by blockade of nitric oxide synthesis"Circulation. 101. 305-310 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koyanagi M, Egashira K, et al.: "Role of transforming growth factor-β1 in cardiovascular inflammatory changes induced by chronic inhibition of nitric oxide synthesis"eypertension. 35. 86-96 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koyanagi M, Egashira K, et al.: "Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis in rats"Circulation. 102. 2243-2248 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitamoto S, Egashira K, et al.: "Increased activity of nuclear factor κB participates to cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis in rats"Circulation. 102. 806-812 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Egashira K, et al.: "Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats. Blockade of MCP-1 activity following intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis"FASEB J. 14. 1974-1978 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitamoto S, Egashira K, et al.: "Chronic inhibition of nitric oxide synthesis in rat increases aortic superoxide anion production through local angiotensin II activity"J Hypertension. 18. 1795-1800 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ni WH, Egashira K, et al.: "Anti-inflammatory and Anti-arteriosclerotic Actions of HMG-CoA Reductase Inhibitors in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis"Circulation Research. 89. 415-421 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kataoka C, Egashira K, et al.: "Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats"Hypertension. 39. 245-250 (2002)

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

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Published: 2003-09-17  

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