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-l synthesis is controlled at the transcriptional level, We report that glucocorticoids increase the pre-pro-endothelin-l gene transcription rate in vascular smooth muscle cells. The effect of glucocorticoids is dose-dependent (EC50 similar to 2-3 nM) and completely blocked by co-incubation with the glucocorticoid antagonist RU 38486. The rise in pp-Et-l 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-l mRNA levels. Nuclear run-on analysis shows that glucocorticoids increase the transcription rate of pre-pro-endothelin-l. Our results suggest a role for glucocorticoids in the regulation of biosynthesis and action of this important vasoactive peptide in vascular smooth muscle cells. (C) 1998 Academic Press.