• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to project page

1999 Fiscal Year Final Research Report Summary

Regulation of gene expression of inducible nitric oxide synthase (iNOS) in cardiovascular system and its molecular mechanism of action

Research Project

Project/Area Number 10470225
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

HINATA Yukio  Tokyo Medical and Dental University, 医学部, 助教授 (50135787)

Co-Investigator(Kenkyū-buntansha) SHICHIRI Masayoshi  Tokyo Medical and Dental University, 医学部, 助手 (10206097)
Project Period (FY) 1998 – 1999
Keywordsnitric oxide (NO) / inducible NO synthase (iNOS) / Vascular Smooth Muscle / atherosclerosis / apoptosis / nuclear factor (NF)-kB / cytokines / glucocorticoid
Research Abstract

Excessive production of NO by iNOS is implicated in the development of endotoxic shock and atherosclerotic lesion. To elucidate the role of iNOS-derived NO, we have studied the molecular mechanisms of iNOS gene expression and its actions in cultured rat vascular smooth muscle cells (VSMC). Transfection of iNOS cDNA construct into VSMC by lipofection caused a massive generation of NO accompanied by apoptosis and inhibition of DNA synthesis, suggesting the role of NO as proapoptotic factor to prevent intimal thickening in atherosclerosis. Addition of NO donors caused massive apoptosis of cultured rat endothelial cells (EC), whose effect was blocked by endothelin-1 (ET-1), suggesting that NO functions as a proapoptotic factor, whereas ET-1 function as an anti-apoptotic factor, thereby conteracting with each other to maintain endothelial integrity.
Inflammatory cytokines, such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, activate nuclear factor (NF)-kB by phosphorylation and degradation of IkBα, thereby leading to transactivation of iNOS gene promoter. However, NO donors inhibited cytokines-induced iNOS gene expression by blocking phosphorylation and subsequent degradation of IkBα, suggesting that endogenous NO generated from iNOS inhibits overexpression of iNOS in an autofeedback fashion. Glucocorticoid also inhibited cytokines-induced iNOS gene expression by blockade of IkBα phosphorylation and degradation. In contrast, nonsteroidal anti-inlflammatory drugs (NSAID), such as aspirin and sodium salicylate, inhibited cytokines-stimulated NO production by blocking (post) translational level without affecting NF-kB activation or iNOS gene transcription. These data suggest that glucocorticoid and NSAID exert their anti-inflammatory effects by blocking NO production via different sites of action.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Suenotu N et al.: "Notriuretic peptides and nitric oxide induce endothelial apoptosis via cyclic GMP-dependent mechanism"Arterioscler. Thranb. Vasc. Biol.. 19. 140-146 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mitaka C et al.: "Important of renal dysfunction in dogs with endotoxemia by a nonselectine endothelin receptor antagonist"Crit. Care Med.. 27. 146-153 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Katsuyama K et al.: "Differential inhibitory actions by glucocorticoud and aspirin on Cyfokine-induced nctric oxide production in VSMC"Endocrinology. 140. 2183-2190 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shichiri M et al.: "Induction of Max by adrenomedullin and CGRP antagonizes endothelial apoptosis"Nol. Endocrinol.. 13. 1353-1363 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Iwasaki H. et al.: "Endothelin-mediated vascular growth requires p42/p44 MAP kinase and p70S6 kinase in transactivation of EGF receptor"Endocrinology. 140. 4659-4668 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Eguchi S et al.: "Intracellular Signalling of angrolensin II induces p70S6 kinase phosphorylation at Ser411 in VSMC"J. Biol. Chem.. 274. 36843-36851 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 平田結喜緒: "心筋保護の臨床-ベットサイトから分子メカニズムまで"南山堂. 11 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 平田結喜緒: "Annual Review 内分泌・代謝 2000"中外医学社. 6 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Suenobu N. et al.: "Natriuretic peptides and nitric oxide induce endothelial apoptosis via cyclic GMP-dependent mechanism"Arlerioscler, Thramb. Vasc. Biol. 19. 140-146 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mitaka C. et al: "Important of renal dysfunction in dogs with endotoxemia by a nonselective endothelin receptor antagonist"Crit. Care. Med.. 27. 146-153 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Katzuyama K. et al.: "Differential inhibitory actions by glucocorticoid and aspirin on cytokine induced nitric oxide production in VSMC"Endocrinology. 140. 2183-2190 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shichiri M. et al.: "Induction of Max by adrenomedullin and CGRR antagonizes endothelial apoptosis"Mol. Endocrinal. 13. 1353-1363 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Iwasaki, H. et al.: "Endothelin-mediated vascular growth requires p42/p44 MtP Kinase and P70S6 Kinase in transactivation of EGF receptor"Endocrinology. 140. 4659-4668 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Eguchi S. et al.: "Intracellular Signaling of angrotensin II induced P70S6 Kinase phosphorylation at Ser 411 in VSMC."J. biol. Chem.. 274. 36843-36851 (1999)

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

URL: 

Published: 2001-10-23  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi