Ligand-dependent activation of ER{beta} lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats.

Abstract

AIMS:

The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERalpha and ERbeta, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ERalpha agonist 16alpha-LE2 improves vascular relaxation, attenuates cardiac hypertrophy, and increases cardiac output without lowering elevated blood pressure in spontaneously hypertensive rats (SHR). Because ERbeta-deficient mice exhibit elevated blood pressure and since the ERbeta agonist 8beta-VE2 attenuated hypertension in aldosterone-salt-treated rats, we have now tested the hypothesis that the isotype-selective ERbeta agonist 8beta-VE2 might be capable of lowering elevated blood pressure in ovariectomized SHR.

METHODS AND RESULTS:

Treatment of ovariectomized SHR with 8beta-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). 8beta-VE2 enhanced aortic ERbeta 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). 8beta-VE2, in contrast to oestradiol, did not enhance cardiac alpha-myosin heavy chain expression.

CONCLUSION:

Ligand-dependent activation of ERbeta confers blood pressure lowering effects in SHR that are superior to those of 17beta-estradiol or the ERalpha agonist 16alpha-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.

• Authors: Virginija Jazbutyte, Paula Anahi Arias-Loza, Kai Hu, Julian Widder, Vijayakumar Govindaraj, Christine von Poser-Klein, Johann Bauersachs, Karl-Heinrich Fritzemeier, Christa Hegele-Hartung, Ludwig Neyses, Georg Ertl, Theo Pelzer
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 77 Issue 4 Pg. 774-81 (Mar 01 2008) ISSN: 0008-6363 [Print] England
• PMID: 18056768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Ligands
• MYH7 protein, rat
• Microfilament Proteins
• Phosphoproteins
• vasodilator-stimulated phosphoprotein
• Estradiol
• Myosin Heavy Chains

Topics

• Animals
• Aorta (drug effects, metabolism)
• Blood Pressure (drug effects)
• Cardiomegaly (etiology, metabolism, physiopathology, prevention & control)
• Cell Adhesion Molecules (genetics, metabolism)
• Disease Models, Animal
• Estradiol (analogs & derivatives, metabolism, pharmacology)
• Estrogen Receptor alpha (metabolism)
• Estrogen Receptor beta (agonists, metabolism)
• Female
• Hemodynamics (drug effects)
• Hypertension (complications, drug therapy, metabolism, physiopathology)
• Ligands
• Microfilament Proteins (genetics, metabolism)
• Myocardium (metabolism, pathology)
• Myosin Heavy Chains (genetics, metabolism)
• Ovariectomy
• Phosphoproteins (genetics, metabolism)
• Rats
• Rats, Inbred SHR
• Uterus (drug effects, metabolism)
• Vasodilation (drug effects)