Glucocorticoids downregulate cyclooxygenase-1 gene expression and prostacyclin synthesis in fetal pulmonary artery endothelium

Prostacyclin (prostaglandin I-2 [PGI(2)]) is a key mediator of pulmonary va scular function during early postnatal life, and its production in the pulm onary vasculature rises markedly during that period because of increasing e xpression of cyclooxygenase type 1 (COX-1), The postnatal rise in COX-1 may be due to the release of inhibition by glucocorticoids, since plasma gluco corticoid levels fall after birth and glucocorticoids decrease PGI, synthes is in certain nonpulmonary cell types. We therefore studied the direct effe cts of dexamethasone (DEX) on COX-1 expression in early-passage ovine fetal pulmonary-artery endothelial cells (PAECs). DEX (10-(10) to 10(-6) mol/L) caused a dose-related decrease in COX-1 mRNA expression that was evident by 24 hours, was maximal at 10(-6) mol/L (50% inhibition), and was not due to changes in mRNA stability. There was a parallel decline in COX-I protein e xpression. COX-1 protein rose following DEX withdrawal, and DEX blunted the stimulatory effect of 17 beta-estradiol on COX-1 expression. DEX alone (10 (-8) mol/L for 48 hours) caused a 93% fall in basal PGI(2) production, and bradykinin- and A23187-stimulated PGI, were diminished 96% and 94%, respect ively. Similarly, PGI(2) synthesis from arachidonic acid fell 86% with DEX; all of the above effects are consistent with COX-1 downregulation. The glu cocorticoid receptor (GR) antagonist mifepristone (RU-486; 10(-6) mol/L) bl ocked the inhibitory effect of DEX, and GR expression was evident by immuno blot analysis. These findings indicate that glucocorticoids downregulate CO X-1 expression and PGI(2) synthesis in fetal PAECs through the activation o f PAEC CR and effects on COX-1 gene transcription. This mechanism may modul ate pulmonary PGI(2) production in the perinatal period, and it may also pl ay a role in the effects of glucocorticoids on the systemic circulation at a variety of ages.