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 synthe sis is controlled at the transcriptional level, We report that glucoco rticoids increase the pre-pro-endothelin-l gene transcription rate in vascular smooth muscle cells. The effect of glucocorticoids is dose-de pendent (EC50 similar to 2-3 nM) and completely blocked by co-incubati on with the glucocorticoid antagonist RU 38486. The rise in pp-Et-l st eady state mRNA levels is rapid and transient with a maximal three-fol d stimulation within one hour of glucocorticoid administration. Glucoc orticoid 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 glucocor ticoids in the regulation of biosynthesis and action of this important vasoactive peptide in vascular smooth muscle cells. (C) 1998 Academic Press.