Prostacyclin (PGI(2)) is a potent vasodilator and inhibitor of platelet agg
regation that is produced by prostacyclin synthase via the cyclooxygenase (
COX) pathway of arachidonic acid metabolism. We investigated the potential
role of COX-2 in the production of vasoactive prostanoids by aortic tissue
in a rabbit model of dietary cholesterol-induced atherosclerosis. COX-1 was
detected as the major isoform by immunoblot analysis in extracts from aort
as of normal and 8 week cholesterol-fed animals with COX-2 being induced in
atherosclerotic plaques from cholesterol-fed animals. Aortic tissue from c
holesterol-fed animals showed decreased levels of basal 6-keto-PGF(1 alpha)
and PGE(2) production as compared to the normal controls but showed no dif
ference with respect to their ability to synthesize these prostanoids in re
sponse to exogenous arachidonic acid. The highly selective COX-2 inhibitors
rofecoxib and the furanone DFP at concentrations of up to 10 mu mol/l had
no effect on the arachidonic acid-dependent production of 6-keto-PGF(1 alph
a), in contrast to indomethacin, which caused a complete inhibition at 0.5
mu mol/l. Celecoxib caused a significant inhibition of 6-keto-PGF(1 alpha)
at 10 mu mol/l but had little effect when the dose was lowered to 1 mu mol/
l. Similar effects of these inhibitors were observed with respect to the pr
oduction of PGE, and no major difference was observed between aortic tissue
s from normal and cholesterol-fed animals with regard to inhibitor sensitiv
ity. These results indicate that in a rabbit model of early stage cardiovas
cular disease, the basal production of 6-keto-PGF1 alpha and PGE(2) by aort
ic tissue is decreased. Furthermore, COX-2 expression is induced in atheros
clerotic plaques and may play a role in altering localized synthesis of pro
stanoids in these lesions but does not appear to significantly impact the a
rachidonic acid-dependent prostacylin production of aortic tissues, which i
s largely mediated by COX-1. (C) 2001 Elsevier Science Ireland Ltd. All rig
hts reserved.