Effects of COX-2 inhibitors on aortic prostacyclin production in cholesterol-fed rabbits

Abstract

Abstract Prostacyclin (PGI 2 ) is a potent vasodilator and inhibitor of platelet aggregation 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 aortas of normal and 8 week cholesterol-fed animals with COX-2 being induced in atherosclerotic plaques from cholesterol-fed animals. Aortic tissue from cholesterol-fed animals showed decreased levels of basal 6-keto-PGF 1α and PGE 2 production as compared to the normal controls but showed no difference with respect to their ability to synthesize these prostanoids in response to exogenous arachidonic acid. The highly selective COX-2 inhibitors rofecoxib and the furanone DFP at concentrations of up to 10 μmol/l had no effect on the arachidonic acid-dependent production of 6-keto-PGF 1α , in contrast to indomethacin, which caused a complete inhibition at 0.5 μmol/l. Celecoxib caused a significant inhibition of 6-keto-PGF 1α at 10 μmol/l but had little effect when the dose was lowered to 1 μmol/l. Similar effects of these inhibitors were observed with respect to the production of PGE 2 and no major difference was observed between aortic tissues from normal and cholesterol-fed animals with regard to inhibitor sensitivity. These results indicate that in a rabbit model of early stage cardiovascular disease, the basal production of 6-keto-PGF 1α and PGE 2 by aortic tissue is decreased. Furthermore, COX-2 expression is induced in atherosclerotic plaques and may play a role in altering localized synthesis of prostanoids in these lesions but does not appear to significantly impact the arachidonic acid-dependent prostacylin production of aortic tissues, which is largely mediated by COX-1.