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

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 17β-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.

Original languageEnglish (US)
Pages (from-to)193-200
Number of pages8
JournalCirculation Research
Volume84
Issue number2
StatePublished - Feb 5 1999

Fingerprint

Cyclooxygenase 1
Epoprostenol
Pulmonary Artery
Glucocorticoids
Endothelium
Down-Regulation
Gene Expression
Dexamethasone
Glucocorticoid Receptors
Mifepristone
Endothelial Cells
Lung
RNA Stability
Calcimycin
Bradykinin
Arachidonic Acid
Blood Vessels
Estradiol
Sheep
Proteins

Keywords

  • Cyclooxygenase-1
  • Endothelium
  • Glucocorticoid
  • Prostacyclin
  • Pulmonary circulation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Glucocorticoids downregulate cyclooxygenase-1 gene expression and prostacyclin synthesis in fetal pulmonary artery endothelium. / Jun, Sandy S.; Chen, Zhong; Pace, Margaret C.; Shaul, Philip W.

In: Circulation Research, Vol. 84, No. 2, 05.02.1999, p. 193-200.

Research output: Contribution to journalArticle

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