RT Journal Article
SR Electronic
T1 Cyclooxygenase-2 Acts as an Endogenous Brake on Endothelin-1 Release by Human Pulmonary Artery Smooth Muscle Cells: Implications for Pulmonary Hypertension
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1147
OP 1153
DO 10.1124/mol.62.5.1147
VO 62
IS 5
A1 Stephen J. Wort
A1 Mandy Woods
A1 Timothy D. Warner
A1 Timothy W. Evans
A1 Jane A. Mitchell
YR 2002
UL http://molpharm.aspetjournals.org/content/62/5/1147.abstract
AB Endothelin-1 is a potent vasoconstrictor and comitogen for vascular smooth muscle. As such, it has been implicated in pulmonary vascular remodeling and in the development of pulmonary hypertension. Prostacyclin has been shown to be an effective therapy for human pulmonary hypertension, reducing morbidity and mortality, although the mechanism of its action is unknown. Here, we show that the combination of TNF-α and IFN-γ induces the release of endothelin-1 from human pulmonary artery smooth muscle cells via increased transcription of prepro endothelin-1. The release of endothelin-1 and the transcription of prepro endothelin-1 mRNA were inhibited by the activity of coinduced cyclooxygenase-2. Endothelin-1 release was also inhibited by a prostacyclin-mimetic (cicaprost). Thus, under inflammatory conditions, in which vascular smooth muscle is an important source of endothelin-1, the induction of cyclooxygenase-2 represents an endogenous “braking” mechanism. In addition, the beneficial effects of prostacyclin in the treatment of pulmonary hypertension may be caused, at least in part, by the inhibition of endothelin-1 release. Finally, we suggest that these observations may help to explain why patients with pulmonary hypertension experience exacerbations after taking indomethacin and that the newly introduced selective cyclooxygenase-2 inhibitors may increase endothelin-1 production in susceptible patients, leading to vascular remodeling and the development of pulmonary hypertension.