Transcriptional regulation of pre-pro-endothelin-1 gene by glucocorticoids in vascular smooth muscle cells.
Endothelin is a potent vasoactive peptide involved in the maintenance of vascular tone and in pathophysiological states. Endothelin-1 synthesis is controlled at the transcriptional level. We report that glucocorticoids increase the pre-pro-endothelin-1 gene transcription rate in vascular smooth muscle cells. The effect of glucocorticoids is dose-dependent (EC50 approximately 2-3 nM) and completely blocked by co-incubation with the glucocorticoid antagonist RU 38486. The rise in pp-Et-1 steady state mRNA levels is rapid and transient with a maximal three-fold stimulation within one hour of glucocorticoid administration. Glucocorticoid treatment does not affect the half-life of pre-pro-endothelin-1 mRNA as shown by actinomycin D studies. Furthermore, cycloheximide treatment concomitantly with RU 28362 did not reverse the stimulatory effect of glucocorticoids on pre-pro-endothelin-1 mRNA levels. Nuclear run-on analysis shows that glucocorticoids increase the transcription rate of pre-pro-endothelin-1. Our results suggest a role for glucocorticoids in the regulation of biosynthesis and action of this important vasoactive peptide in vascular smooth muscle cells.
Morin
C
C
Department of Medicine, Faculty of Medicine, Sherbrooke University, Quebec, Canada.
Asselin
C
C
Boudreau
F
F
Provencher
P H
PH
D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D019332:Endothelin-1; D016232:Endothelins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
D000732:Androstanols; D019332:Endothelin-1; D016232:Endothelins; D005938:Glucocorticoids; D006727:Hormone Antagonists; D011498:Protein Precursors; D012333:RNA, Messenger; D003609:Dactinomycin; D015735:Mifepristone; C049154:11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one; D003513:Cycloheximide