(Circulation. 2000;102:1828.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Differential Effects of Estrogen and Progesterone on AT1 Receptor Gene Expression in Vascular Smooth Muscle Cells
From the Klinik III für Innere Medizin and the Institut für Physiologie (H.S.), Universität zu Köln, Cologne, Germany.
Correspondence to Dr Georg Nickenig, Klinik III für Innere Medizin, Joseph-Stelzmann-Straße 9, 50924 Köln, Germany. E-mail georg.nickenig{at}uni-koeln.de
Background—The beneficial vasoprotective effects of a postmenopausal estrogen replacement therapy may be prevented by a concomitant administration of progestins. To investigate the differential effects of estrogens and progesterone, we examined their influence on AT1 receptor gene expression in vascular smooth muscle cells (VSMCs).
Methods and Results—17ß-Estradiol caused downregulation of
AT1 receptor mRNA expression to 46±14%, whereas
progesterone led to a significant upregulation to 201±29%, as
assessed by Northern analysis. Western blots revealed that
estrogen induced a downregulation and progesterone an upregulation of
the AT1 receptor protein. Estrogen-induced decrease of
AT1 receptor expression was mediated through activation of
estrogen receptors. Nuclear run-on assays revealed that 17ß-estradiol
did not alter AT1 receptor mRNA transcription rate, whereas
progesterone caused an enhanced AT1 receptor mRNA
transcription rate. 17ß-Estradiol decreased the AT1
receptor mRNA half-life from 5 to 2 hours, whereas progesterone induced
a stabilization of AT1 receptor mRNA to a half-life of 10
hours. Preincubation of VSMCs with PD98059, SB203580, herbimycin,
wortmannin, or
N
-nitro-L-arginine suggested
that 17ß-estradiol caused AT1 receptor downregulation
through nitric oxide–dependent pathways. Progesterone caused
AT1 receptor overexpression via PI3-kinase
activation. Angiotensin II–induced release of reactive
oxygen species was inhibited by estrogens. Progesterone itself enhanced
the production of reactive oxygen species.
Conclusions—Because AT1 receptor regulation plays a pivotal role in the pathogenesis of hypertension and atherosclerosis, the differential effects of estrogen and progesterone on the expression of this gene may in part explain the potentially counteracting effects of these reproductive hormones on the incidence of postmenopausal cardiovascular diseases.
Key Words: receptors • angiotensin • muscle, smooth • hypertension • atherosclerosis • hormones
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