14,15-epoxyeicosatrienoic acid inhibits prostaglandin E-2 production in vascular smooth muscle cells

14,15-Epoxyeicosatrienoic acid (EET), a cytochrome P-450 epoxygenase produc t of arachidonic acid (AA), reduced PGE(2) formation by 40-75% in porcine a ortic and murine brain microvascular smooth muscle cells. The inhibition wa s reversed 6-10 h after removal of 14,15-EET from the medium and was regioi someric specific; 8,9-EET produced a smaller effect, whereas 11,12- and 5,6 -EET were ineffective. Although the cells converted 14,15-EET to 14,15-dihy droxyeicosatrienoic acid (14,15-DHET), 14,15-DHET did not inhibit PGE(2) fo rmation, and the 14,15-EET-induced inhibition was potentiated by 4-phenylch alcone oxide, an epoxide hydrolase inhibitor. The inhibition occurred when substrate amounts of AA were used and was not accompanied by enhanced produ ction of other PGs, suggesting an effect on PGH synthase; however, in murin e cells, 14,15-EET did not reduce PGH synthase mRNA or protein. Moreover, t he 14,15-EET-induced decrease in PGE(2) production was overcome by increasi ng the concentration of AA, but not oleic acid (which is not a substrate fo r PGH synthase). These findings suggest that 14,15-EET competitively inhibi ts PGH synthase activity in vascular smooth muscle cells. The 14,15-EET-ind uced inhibition of PGE(2) production resulted in potentiation of platelet-d erived growth factor-induced smooth muscle cell proliferation, suggesting t hat the competitive inhibition of PGK synthase by 14,15-EET can affect grow th responses in smooth muscle cells.