Nitric oxide regulates shear stress-induced early growth response-1: Expression via the extracellular signal-regulated kinase pathway in endothelial cells

J. J. Chiu, B. S. Wung, H. J. Hsieh, L. W. Lo, D. L. Wang

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Endothelial cells (ECs) subjected to shear stress constantly release nitric oxide(NO). The effect of NO on shear stress-induced endothelial responses was examined. ECs subjected to shear stress induced a transient and shear force-dependent increase in early growth response-1 (Egr-1) mRNA levels. Treatment of ECs with an NO donor, S-nitroso-N-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1), inhibited this shear stress- induced Egr-1 expression. Conversely, an NO synthase inhibitor to ECs, N(G)- monomethyl-L-arginine, augmented this Egr-1 expression. NO modulation of Egr- 1 expression was demonstrated by functional analysis of Egr-1 promoter activity using a chimera containing the Egr-1 promoter region (-698 bp) and reporter gene luciferase. In contrast to the enhanced promoter activity after N(G)-monomethyl-L-arginine treatment, shear stress-induced Egr-1 promoter activity was attenuated after ECs were treated with an NO donor. ECs cotransfected with a dominant negative mutant of Ras (RasN17), Raf-1 (Raf301), or a catalytically inactive mutant of extracellular signal- regulated kinase (ERK)-2 (mERK) inhibited shear stress-induced Egr-1 promoter activity. NO modulation of the signaling pathway was shown by its inhibitory effect on shear stress-induced ERK1/ERK2 phosphorylation and activity. This inhibitory effect was further substantiated by the inhibition of NO on both the shear stress-induced transcriptional activity of Elk-1 (an ERK substrate) and the promoter activity of a reporter construct containing serum response element. NO-treated ECs resulted in a reduction of binding of nuclear proteins to the Egr-1 binding sequences in the platelet-derived growth factor-A promoter region. These results indicate that shear stress-induced Egr-1 expression is modulated by NO via the ERK signaling pathway in ECs. Our findings support the importance of NO as a negative regulator in endothelial responses to hemodynamic forces.

Original languageEnglish
Pages (from-to)238-246
Number of pages9
JournalCirculation Research
Volume85
Issue number3
DOIs
Publication statusPublished - Aug 6 1999
Externally publishedYes

Keywords

  • Egr-1
  • Endothelial cell
  • Nitric oxide
  • Shear stress
  • Signaling pathway

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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