Cardiovascular Research Advance Access originally published online on December 4, 2007
Cardiovascular Research 2008 77(4):774-781; doi:10.1093/cvr/cvm081
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Ligand-dependent activation of ERβ lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats
1 Department of Medicine, University of Würzburg, Josef-Schneider Str. 2, D-97080 Würzburg, Germany
2 Schering AG, Berlin, Germany
3 Division of Cardiology, University of Manchester, Manchester, UK
* Corresponding author. Tel: +49 931 201 36112; fax: +49 931 201 36212. E-mail address: pelzer_t{at}klinik.uni-wuerzburg.de
Aims: The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ER
and ERβ, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ER agonist 16-LE2 improves vascular relaxation, attenuates cardiac hypertrophy, and increases cardiac output without lowering elevated blood pressure in spontaneously hypertensive rats (SHR). Because ERβ-deficient mice exhibit elevated blood pressure and since the ERβ agonist 8β-VE2 attenuated hypertension in aldosterone-salt-treated rats, we have now tested the hypothesis that the isotype-selective ERβ agonist 8β-VE2 might be capable of lowering elevated blood pressure in ovariectomized SHR.
Methods and results: Treatment of ovariectomized SHR with 8β-VE2 for 12 weeks conferred no uterotrophic effects but lowered elevated systolic blood pressure (–38 ± 5 mmHg, n = 31, P < 0.001 vs. placebo) as well as peripheral vascular resistance (–31.3 ± 4.6%, P < 0.001 vs. placebo). 8β-VE2 enhanced aortic ERβ expression (+75.7 ± 7.1%, P < 0.01 vs. placebo), improved NO-dependent vasorelaxation, augmented phosphorylation of the vasodilator-stimulated phosphoprotein in isolated aortic rings (P < 0.05 vs. placebo), increased cardiac output (+20.4 ± 2.5%, P < 0.01 vs. placebo), and attenuated cardiac hypertrophy (–22.2 ± 3.2%, p < 0.01 vs. placebo). 8β-VE2, in contrast to oestradiol, did not enhance cardiac -myosin heavy chain expression.
Conclusion: Ligand-dependent activation of ERβ confers blood pressure lowering effects in SHR that are superior to those of 17β-estradiol or the ER agonist 16-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.
KEYWORDS Oestrogen receptor; Myocardium; Hypertrophy; Hypertension
Time for primary review: 26 days