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Am J Physiol Heart Circ Physiol (July 8, 2004). doi:10.1152/ajpheart.00323.2004
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Submitted on April 1, 2004
Accepted on June 24, 2004

Nitric Oxide Donor Induces Temporal and Dose-Dependent Reduction of Gene Expression in Human Endothelial Cells

Branko Braam1*, Remmert de Roos1, Adele Dijk1, Peter Boer1, Jan Andries Post2, Patrick PCW Kemmeren3, Frank CP Holstege3, Hans AR Bluyssen1, and Hein A. Koomans1

1 Department of Nephrology and Hypertension, Univiversity of Medical Center Utrecht, Utrecht, The Netherlands
2 Department of Molecular Cell Biology, University of Medical, Utrecht, The Netherlands
3 Genomic Laboratory, University of Medical Center Utrecht, Utrecht, The Netherlands

* To whom correspondence should be addressed. E-mail: g.b.braam{at}azu.nl.

The present study tested the hypothesis that acute increases in NO exert substantial influences on gene transcription in EC via guanylyl cyclase (GC). Human umbilical veins EC (HUVEC) were exposed to 0.1, 1 and 10 mM of sodium-nitroprusside (SNP) for 4 hours and to 1 mM SNP or 250 uM of DETA-NONOate for 2, 4, 8 and 24 hours. Also, cells were exposed to DETA-NONOate in the presence and absence of GC inhibitor 10 uM ODQ for 4 hours. RNA was isolated, reverse transcribed, Cy3- and Cy5-labeled and analyzed using cDNA microarrays. Increasing doses of SNP predominantly depressed gene expression in HUVEC. Genes function was related to growth, adhesion and cell structure. DETA-NONOate evoked a wave of expression changes (maximum at 4 hours), with a remarkable downregulation of the transcription factors MSX1, RELB and Egr-1. Both SNP- and DETA-NONOate-induced gene expression had faded after 24 hours, despite continued elevation of cGMP in the medium (of the SNP treated cells). Co-administration of ODQ decreased many, but not all of the transcriptional responses to DETA-NONOate. NO pronouncedly depressed EC gene expression, in particular of transcription factors. The observation that many, but not all, transcriptional changes induced by NO could be inhibited by inhibition of GC, indicates the presence of GC-independent NO actions on gene expression. Thus, EC gene expression responds to NO, however, the transcriptional response fades during prolonged exposure. This could allow the endothelial cell to respond to increased shear, without vigorous changes in gene expression.




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