(Hypertension. 2001;37:640.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Estradiol Metabolites Inhibit Endothelin Synthesis by an Estrogen Receptor-Independent Mechanism
From the Department of Obstetrics and Gynecology (R.K.D., P.J.K., B.I., M.R.), Clinic for Endocrinology, University Hospital, Zurich, Switzerland, and Departments of Medicine (R.K.D., E.K.J.), and Pharmacology (E.K.J.) Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Correspondence to Raghvendra K. Dubey, PhD, Department of Obstetrics and Gynecology, Clinic for Endocrinology, D215, NORD-1; Frauenklinik, University Hospital Zurich, 8091 Zurich, Switzerland. E-mail raghvendra.Dubey{at}fhk.usz.ch
Estradiol
inhibits endothelin-1 synthesis, an effect that may contribute to the
cardiovascular protective effects of estradiol. Recent
findings that estradiol inhibits neointima formation in
mice lacking estrogen receptors suggests that the
cardiovascular protective effects of estradiol may be
mediated by means of an estrogen receptor-independent mechanism.
Because 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of
estradiol with little/no affinity for estrogen receptors, are more
potent than estradiol in inhibiting vascular smooth muscle cell growth,
we investigated whether these metabolites also inhibit endothelin-1
synthesis by means of an receptor-independent mechanism. Treatment of
porcine coronary artery endothelial cells for 4
to 24 hours with 0.001 to 1 µmol/L of estradiol, 2-hydroxyestradiol,
or 2-methoxyestradiol concentration-dependently inhibited basal as well
as serum-induced (2.5%), TNF
-induced (10 ng/mL),
angiotensin II–induced (100 nmol/L), and thrombin-induced
(4 U/mL) endothelin-1 synthesis. Estradiol, 2-hydroxyestradiol, and
2-methoxyestradiol also inhibited serum-induced
mitogen-activated protein kinase activity. As compared with
estradiol, its metabolites were more potent in inhibiting endothelin-1
secretion and mitogen activated protein kinase activity. The
inhibitory effects of 2-hydroxyestradiol and
2-methoxyestradiol on endothelin-1 release and
mitogen-activated protein kinase activity were not blocked by
ICI182780 (50 µmol/L), an estrogen receptor antagonist.
Our findings indicate that the estradiol metabolites 2-hydroxyestradiol
and 2-methoxyestradiol potently inhibit endothelin-1 synthesis by means
of an estrogen receptor-independent mechanism. This effect of estradiol
metabolites may be mediated by inhibition of mitogen activated
protein kinase activity and may contribute to the cardioprotective
effects of estradiol.
Key Words: postmenopause • endothelial cells • vascular remodeling • cardiovascular disease • estradiol metabolites • coronary artery
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