From the Klinik III für Innere Medizin, Universität zu
Köln (G.N., A.T.B., K.S., S.R., A.S., F.B., M.B.), and the Medizinische
Universitäts-Poliklinik, Bonn (C.G., S.K., H.V.), Germany; and the
Departments of Pharmacology (J.F.M.S.) and Pathology (M.J.A.P.D.),
Cardiovascular Research Institute, University of Maastricht, the Netherlands.
Drs Nickenig and Bäumer contributed equally to this study.
Correspondence to Dr Georg Nickenig, Klinik III für Innere Medizin, Joseph-Stelzmann-Str 9, 50924 Köln, Germany. E-mail georg.nickenig{at}uni-koeln.de
Abstract
Background—The AT1
receptor has been implicated in the pathogenesis of hypertension and
atherosclerosis. Estrogen deficiency is also associated
with cardiovascular diseases. Therefore, we examined
the AT1 receptor gene expression in ovariectomized rats
with and without estrogen replacement therapy and the influence of
estrogen on AT1 receptor expression in cultured vascular
smooth muscle cells.
Methods and Results—Rat aortic tissue was examined 5 weeks after
ovariectomy. In one group, estrogen (1.7 mg estradiol) was administered
during the 5-week period. Functional experiments assessed
angiotensin II–induced contraction of aortic rings.
AT1 receptor mRNA levels were measured by quantitative
polymerase chain reaction and Northern blotting. AT1
receptor density was assessed by radioligand binding
assays. These techniques were also applied in cultured vascular smooth
muscle cells. The efficacy of angiotensin II on
vasoconstriction was significantly increased in aortas from
ovariectomized rats. As assessed by radioligand binding
assays, AT1 receptor density was increased to 160% without
changes in receptor affinity during estrogen deficiency.
AT1 receptor mRNA levels were consistently
increased to 187% in ovariectomized rats compared with sham-operated
animals. Estrogen substitution therapy in ovariectomized rats reversed
this AT1 receptor overexpression. To explore the underlying
mechanisms, the direct influence of estradiol on AT1
receptor expression was investigated in VSMCs. Estradiol (1
µmol/L) led to a time-dependent downregulation of AT1
receptor mRNA, with a maximum of 33.3% at 12 hours. There was a
correlative decrease in AT1 receptor density.
Conclusions—This novel observation of estrogen-induced
downregulation of AT1 receptor expression could explain the
association of estrogen deficiency with hypertension and
atherosclerosis, because activation of the
AT1 receptor plays a key role in the regulation of blood
pressure, fluid homeostasis, and vascular cell growth.
© 1998 American Heart Association, Inc.
Brief Rapid Communication
Estrogen Modulates AT1 Receptor Gene Expression In Vitro and In Vivo
Key Words: angiotensin • hypertension • hormones • genes • muscle, smooth • atherosclerosis
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 D. A. Lewis, M. P. Bracamonte, K. S. Rud, and V. M. Miller Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Effects of sex and ovariectomy on responses to platelets in porcine femoral veins J Appl Physiol, December 1, 2001; 91(6): 2823 - 2830. [Abstract] [Full Text] [PDF]
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C. K. Roberts, N. D. Vaziri, and R. J. Barnard Protective effects of estrogen on gender-specific development of diet-induced hypertension J Appl Physiol, November 1, 2001; 91(5): 2005 - 2009. [Abstract] [Full Text] [PDF]
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M. van Eickels, C. Grohe, J. P.M. Cleutjens, B. J. Janssen, H. J.J. Wellens, and P. A. Doevendans 17{beta}-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy Circulation, September 18, 2001; 104(12): 1419 - 1423. [Abstract] [Full Text] [PDF]
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A. PATZAK, R. MROWKA, E. STORCH, B. HOCHER, and P. B. PERSSON Interaction of Angiotensin II and Nitric Oxide in Isolated Perfused Afferent Arterioles of Mice J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1122 - 1127. [Abstract] [Full Text]
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 A. M. Sharma, V. Homuth, and F. C. Luft Hormone replacement therapy and blood pressure in normotensive and hypertensive women Nephrol. Dial. Transplant., May 1, 2001; 16(5): 888 - 890. [Full Text] [PDF]
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J. F. Reckelhoff Gender Differences in the Regulation of Blood Pressure Hypertension, May 1, 2001; 37(5): 1199 - 1208. [Abstract] [Full Text] [PDF]
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 S. Wassmann, U. Laufs, A. T. Bäumer, K. Müller, C. Konkol, H. Sauer, M. Böhm, and G. Nickenig Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase Mol. Pharmacol., March 1, 2001; 59(3): 646 - 654. [Abstract] [Full Text]
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R. K. Dubey and E. K. Jackson Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms Am J Physiol Renal Physiol, March 1, 2001; 280(3): F365 - F388. [Abstract] [Full Text] [PDF]
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S. Wassmann, A. T. Baumer, K. Strehlow, M. van Eickels, C. Grohe, K. Ahlbory, R. Rosen, M. Bohm, and G. Nickenig Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats Circulation, January 23, 2001; 103(3): 435 - 441. [Abstract] [Full Text] [PDF]
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P. J. W. Smith, O. Ornatsky, D. J. Stewart, P. Picard, F. Dawood, W.-H. Wen, P. P. Liu, D. J. Webb, and J. C. Monge Effects of Estrogen Replacement on Infarct Size, Cardiac Remodeling, and the Endothelin System After Myocardial Infarction in Ovariectomized Rats Circulation, December 12, 2000; 102(24): 2983 - 2989. [Abstract] [Full Text] [PDF]
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D. M. Roesch, Y. Tian, W. Zheng, M. Shi, J. G. Verbalis, and K. Sandberg Estradiol Attenuates Angiotensin-Induced Aldosterone Secretion in Ovariectomized Rats Endocrinology, December 1, 2000; 141(12): 4629 - 4636. [Abstract] [Full Text] [PDF]
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I. Hernandez, J. L. Delgado, J. Diaz, T. Quesada, M. J. G. Teruel, M. C. Llanos, and L. F. Carbonell 17beta -Estradiol prevents oxidative stress and decreases blood pressure in ovariectomized rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1599 - R1605. [Abstract] [Full Text] [PDF]
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G. Nickenig, K. Strehlow, S. Wassmann, A. T. Baumer, K. Albory, H. Sauer, and M. Bohm Differential Effects of Estrogen and Progesterone on AT1 Receptor Gene Expression in Vascular Smooth Muscle Cells Circulation, October 10, 2000; 102(15): 1828 - 1833. [Abstract] [Full Text] [PDF]
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 C. Muller, A. Reddert, S. Wassmann, K. Strehlow, M. Bohm, and G. Nickenig Insulin-like growth factor induces up-regulation of AT1-receptor gene expression in vascular smooth muscle cells Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 273 - 277. [Abstract] [PDF]
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M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger International Union of Pharmacology. XXIII. The Angiotensin II Receptors Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472. [Abstract] [Full Text] [PDF]
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 M. Schwemmer, O. Sommer, R. Koeckerbauer, and E. Bassenge Cardiovascular Dysfunction in Hypercholesterolemia Associated With Enhanced Formation of ATI-Receptor and of Eicosanoids Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(1): 59 - 68. [Abstract] [PDF]
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K. Takeda, T. Ichiki, Y. Funakoshi, K. Ito, and A. Takeshita Downregulation of Angiotensin II Type 1 Receptor by All-trans Retinoic Acid in Vascular Smooth Muscle Cells Hypertension, January 1, 2000; 35(1): 297 - 302. [Abstract] [Full Text] [PDF]
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J. F. Reckelhoff, H. Zhang, and K. Srivastava Gender Differences in Development of Hypertension in Spontaneously Hypertensive Rats : Role of the Renin-Angiotensin System Hypertension, January 1, 2000; 35(1): 480 - 483. [Abstract] [Full Text] [PDF]
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S. Hugel, M. Reincke, H. Stromer, J. Winning, M. Horn, C. Dienesch, P. Mora, H. H. H. W. Schmidt, B. Allolio, and S. Neubauer Evidence against a role of physiological concentrations of estrogen in post-myocardial infarction remodeling J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1427 - 1434. [Abstract] [Full Text] [PDF]
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 M. E. Mendelsohn and R. H. Karas The Protective Effects of Estrogen on the Cardiovascular System N. Engl. J. Med., June 10, 1999; 340(23): 1801 - 1811. [Full Text] [PDF]
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 V M Miller Gender and vascular reactivity Lupus, June 1, 1999; 8(5): 409 - 415. [Abstract] [PDF]
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M. L Kuroski de Bold Estrogen, natriuretic peptides and the renin-angiotensin system Cardiovasc Res, March 1, 1999; 41(3): 524 - 531. [Abstract] [Full Text] [PDF]
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S. K. Das, J. Tan, S. Raja, J. Halder, B. C. Paria, and S. K. Dey Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-alpha and -beta J. Biol. Chem., September 8, 2000; 275(37): 28834 - 28842. [Abstract] [Full Text] [PDF]
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K. J. Scheidegger, B. Cenni, D. Picard, and P. Delafontaine Estradiol Decreases IGF-1 and IGF-1 Receptor Expression in Rat Aortic Smooth Muscle Cells. MECHANISMS FOR ITS ATHEROPROTECTIVE EFFECTS J. Biol. Chem., December 1, 2000; 275(49): 38921 - 38928. [Abstract] [Full Text] [PDF]
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G. Nickenig, F. Michaelsen, C. Muller, A. Berger, T. Vogel, A. Sachinidis, H. Vetter, and M. Bohm Destabilization of AT1 Receptor mRNA by Calreticulin Circ. Res., January 11, 2002; 90(1): 53 - 58. [Abstract] [Full Text] [PDF]
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