Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism

Estradiol inhibits endothelin-l synthesis, an effect that may contribute to the cardiovascular protective effects of estradiol. Recent findings chat e stradiol inhibits neointima formation in mice lacking estrogen receptors su ggests that the cardiovascular protective effects of estradiol may be media ted by means of an estrogen receptor-independent mechanism. Because 2-hydro xyestradiol and 2-methoxyestradiol, metabolites of estradiol with little/no affinity for estrogen receptors, are mon potent than estradiol in inhibiti ng Vascular smooth muscle cell growth, we investigated whether these metabo lites also inhibit endothelin-1 synthesis by means of an receptor-independe nt mechanism. Treatment of porcine coronary artery endothelial cells for 4 to 24 hours with 0.001 to 1 mu mol/L of estradiol, 2-hydroxyestradiol, or 2 -methoxyestradiol concentration-dependently inhibited basal as well as seru m-induced (2.5%), TNF alpha -induced (10 ng/mL), angiotensin II-induced (10 0 nmol/L), and thrombin-induced (4 U/mL) endothelin-l synthesis, Estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol also inhibited serum-induced mi togen-activated protein kinase activity. As compared with estradiol, its me tabolites were more potent in inhibiting endothelin-l secretion and mitogen activated protein kinase activity. The inhibitory effects of 2-hydroxyestr adiol and 2-methoxyestradiol on endothelin-1 release and mitogen-activated protein kinase activity were not blocked by ICI182780 (50 mu mol/L), an est rogen receptor antagonist. Our findings indicate that the estradiol metabol ites 2-hydroxyestradiol and 2-methoxyestradiol potently inhibit endothelin- l synthesis by means of an estrogen receptor-independent mechanism. This ef fect of estradiol metabolites may be mediated by inhibition of mitogen acti vated protein kinase activity and may contribute to the cardioprotective ef fects of estradiol.