© 1999 American Heart Association, Inc.
Original Contribution |
Nitric Oxide Regulates Shear Stress–Induced Early Growth Response-1
Expression via the Extracellular Signal–Regulated Kinase Pathway in Endothelial Cells
From the Cardiovascular Division (J.J.C., B.S.W., L.W.L., D.L.W.), Institute of Biomedical Sciences, Academia Sinica, and Department of Chemical Engineering (H.J.H.), National Taiwan University, Taipei, Taiwan, ROC.
Correspondence to Dr Danny Ling Wang, Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529 Taiwan, ROC. E-mail lingwang{at}ibms.sinica.edu.tw
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, NG-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 NG-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.
Key Words: Egr-1 • endothelial cell • nitric oxide • shear stress • signaling pathway
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