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(Circulation Research. 1999;84:193-200.)
© 1999 American Heart Association, Inc.

Original Contribution

Glucocorticoids Downregulate Cyclooxygenase-1 Gene Expression and Prostacyclin Synthesis in Fetal Pulmonary Artery Endothelium

Sandy S. Jun, Zhong Chen, Margaret C. Pace, Philip W. Shaul

From the Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Tex.

Correspondence to Philip W. Shaul, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9063. E-mail pshaul{at}mednet.swmed.edu

Abstract—Prostacyclin (prostaglandin I₂ [PGI₂]) is a key mediator of pulmonary vascular function during early postnatal life, and its production in the pulmonary vasculature rises markedly during that period because of increasing expression of cyclooxygenase type 1 (COX-1). The postnatal rise in COX-1 may be due to the release of inhibition by glucocorticoids, since plasma glucocorticoid levels fall after birth and glucocorticoids decrease PGI₂ synthesis in certain nonpulmonary cell types. We therefore studied the direct effects 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-1 protein expression. COX-1 protein rose following DEX withdrawal, and DEX blunted the stimulatory effect of 17ß-estradiol on COX-1 expression. DEX alone (10^–8 mol/L for 48 hours) caused a 93% fall in basal PGI₂ production, and bradykinin- and A23187-stimulated PGI₂ were diminished 96% and 94%, respectively. Similarly, PGI₂ synthesis from arachidonic acid fell 86% with DEX; all of the above effects are consistent with COX-1 downregulation. The glucocorticoid receptor (GR) antagonist mifepristone (RU-486; 10^–6 mol/L) blocked the inhibitory effect of DEX, and GR expression was evident by immunoblot analysis. These findings indicate that glucocorticoids downregulate COX-1 expression and PGI₂ synthesis in fetal PAECs through the activation of PAEC GR and effects on COX-1 gene transcription. This mechanism may modulate pulmonary PGI₂ production in the perinatal period, and it may also play a role in the effects of glucocorticoids on the systemic circulation at a variety of ages.

Key Words: cyclooxygenase-1 • endothelium • glucocorticoid • prostacyclin • pulmonary circulation

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