Published online before print June 11, 2007, doi: 10.1161/HYPERTENSIONAHA.106.084798
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(Hypertension. 2007;50:432.)
© 2007 American Heart Association, Inc.
Original Articles |
Both Estrogen Receptor Subtypes, 
and ß, Attenuate Cardiovascular Remodeling in Aldosterone Salt–Treated Rats
From the Medizinische Klinik I (P-A.A.-L., K.H., C.D., V.J., T.P.), University of Würzburg, Würzburg, Germany; Integrated Functional Genomics (A.M.M., S.K.), IZKF University of Münster, Münster, Germany; Division of Cardiology (L.N.), University of Manchester, Manchester, United Kingdom; and Schering AG (C.H-H., K.H.F.), Berlin, Germany.
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Abstract |
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Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart disease requires more precise information on the role of both estrogen receptor (ER) subtypes, ER
and ERß. Therefore, we determined whether selective activation of ER or of ERß would confer redundant, specific, or opposing effects on cardiovascular remodeling in aldosterone salt–treated rats. The ER agonist 16-LE2, the ERß agonist 8ß-VE2, and the nonselective estrogen receptor agonist 17ß-estradiol lowered elevated blood pressure, cardiac mass, and cardiac myocyte cross-sectional areas, as well as increased perivascular collagen accumulation and vascular osteopontin expression in ovariectomized rats receiving chronic aldosterone infusion plus a high-salt diet for 8 weeks. Uterus atrophy was prevented by 16-LE2 and 17ß-estradiol but not by 8ß-VE2. Cardiac proteome analyses by 2D gel electrophoresis, mass spectrometry, and peptide sequencing identified specific subsets of proteins involved in cardiac contractility, energy metabolism, cellular stress response and extracellular matrix formation that were regulated in opposite directions by aldosterone salt treatment and by different estrogen receptor agonists. We conclude that activation of either ER or ERß protects the cardiovascular system against the detrimental effects of aldosterone salt treatment and confers redundant, as well as specific, effects on cardiac protein expression. Nonfeminizing ERß agonists such as 8ß-VE2 have a therapeutic potential in the treatment of hypertensive heart disease.
Key Words: aldosterone • estrogen • proteomics • hypertrophy • inflammation
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Introduction |
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Estrogens and mineralocorticoids act on the cardiovascular system via specific cognate receptors, the mineralocorticoid receptor (MR), and 2 distinct estrogen receptor (ER) subtypes, ER
and ERß. Both ER and ERß, as well as the MR, are related members of the nuclear hormone receptor family, which play important roles and may functionally interact in blood pressure maintenance and in the adaptive response of cardiac muscle toward increased workload and injury. Ligand-dependent activation of the MR by aldosterone promotes sodium and water reabsorption via the kidney and the colonic mucosa. However, elevated aldosterone serum levels in combination with a high-salt diet or altered MR expression promote hypertension and cardiac remodeling including perivascular inflammation, cardiac fibrosis, and cardiac hypertrophy.1–5 Activation of the MR in patients with chronic heart failure represents part of a maladaptive response that triggers a vicious cycle after cardiac injury. In support of this concept, MR antagonists such as spironolactone or eplerenone have been shown to ameliorate the symptoms and to prolong survival in patients with advanced chronic heart failure.6–8 The observation that serum aldosterone levels correlate positively with left ventricular hypertrophy and left ventricular mass index in women but not in men suggests important interactions between estrogen and MR signaling.9,10 Recently we were able to support this concept by showing that the nonselective ER agonist 17ß-estradiol protects aldosterone salt–treated (AST) rats from classical features of MR-mediated cardiovascular injury.11
The observation that uterus atrophy occurred in ER- but not in ERß-deficient mice provided the first evidence for different physiological functions of ER and ERß.12 However, both ER subtypes are also capable of mediating redundant functions in augmenting vascular NO generation.13,14 Therefore, a more accurate understanding of how estrogens protect against the development of cardiovascular disease depends directly on a more detailed knowledge on specific, redundant, and eventually also opposing functions of both ER subtypes.15,16
The divergent role of both ER subtypes in different tissues promoted the development of potent, isotype-selective agonists for ER and for ERß, such as the ER agonist 16-LE2 and the ERß agonist 8ß-VE2. These ligands were synthesized based on discrete differences in the 3D structure of the ligand-binding pocket of ER and ERß and confer biological effects that are in direct line with the function of ER and ERß in reproductive organs.17,18 Herein, we report that selective activation of either ER or of ERß by isotype-specific agonists protects the rodent heart against aldosterone salt-treatment–induced hypertension, vascular inflammation, and cardiac hypertrophy. We also report on the identification of proteins that are differentially expressed in the heart in response to the activation of the MR, ER, and ERß.
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Methods |
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Animal Treatment
Sixty female Wistar rats obtained from IFFA CREDO (Lyon, France) at the age of 12 weeks were randomly divided into 6 groups: group 1, sham ovariectomy, placebo injections; group 2, ovariectomy, osmotic minipump containing carrier solution, placebo injection. Animals in groups 3 to 6 were ovariectomized and uninephrectomized and received continuous aldosterone infusion via osmotic minipumps (Alzet model 2004; 0.75 µg/h) for 8 weeks together with a high-salt diet (1% NaCl added to tap) plus daily subcutaneous injections of the following: group 3, placebo; group 4, 17ß-estradiol (2 µg/kg per day); group 5, 16
-LE2 (selective ER agonist, 30 µg/kg per day); and group 6, 8ß-VE2 (selective ERß agonist, 100 µg/kg per day). For information on the binding affinities of 16-LE2 and 8ß-VE2 to steroid hormone receptors other than ER and ERß, please see the online supplemental data (available at http://hyper. ahajournals.org). Treatment with aldosterone plus salt and with different estrogens was initiated immediately after ovariectomy and continued for 12 weeks. The dose of 17ß-estradiol was chosen to achieve physiological serum estradiol levels, and 16-LE2 and 8ß-VE2 were injected in pharmacological dosages at which both ligands are still ER subtype selective.18 All of the protocols were reviewed and accepted by the local ethics committee and performed in accordance with the current National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Hemodynamic Measurements
Invasive hemodynamic measurements were performed as described before under light isoflurane anesthesia and spontaneous respiration.19 Body weight, heart weight, uterus weight, and kidney weight were determined after hemodynamic analysis. Relative heart weight was calculated from absolute heart weight and tibia length.20 Estradiol and angiotensin II serum levels were determined by radio immunoassays according to the manufacturer’s instructions (estradiol: DPC-Biermann; angiotensin II: Peninsula).
Morphometry
Perivascular collagen accumulation was quantified in each animal around 
6 individual coronary arteries in 3 nonconsecutive sections (total measurements: 972 arteries), and cardiac myocyte cross-sectional areas were determined in all of the rats (total: 4320 myocytes) according to published protocols.11 Media cross-sectional areas of the thoracic aorta were calculated by manual tracing of the internal elastic lamina and the external limit of the media using the Image J software in 3 independent sections from 3 specimens from each animal (total measurements: 175 aortas).11
Immunohistochemistry
Aortic cross-sections were stained for osteopontin according to published protocols.11 Each slide was compared with an adjacent section in which primary antibodies were omitted. Immunostainings for osteopontin were quantified using the Scion software. At least 3 sections per specimen with 3 fields of view per section were analyzed in 4 animals per group (total measurements: 216 sections).
2D Gel Electrophoresis and Protein Analysis
Protein extracts from the left ventricle were subjected to 2D gel electrophoresis, and image acquisition and data analysis were performed following general Amersham protocols. Three extracts that were differentially labeled with fluorescent dyes containing Cy1, Cy2, or Cy3 were loaded and analyzed simultaneously on a single gel (1: internal standard, Cy2; 2: ovariectomized rat [ovx] –AST–placebo, Cy3; and 3: one of the following: ovx–AST–17ß-estradiol, ovx–AST–16-LE2, or ovx–AST–8ß-VE2=Cy5). Protein expression patterns were determined in 3 animals per group, and spot intensities were compared with the internal reference group (ovx–AST–placebo) in which spot intensity was set to ±1. Protein spots were excised from preparative gels, and peptide mapping by matrix assisted laser desorption ionization-time of flight was performed on a TofSpec 2E instrument. Peptide sequencing was carried out on an Esquire3000 ion trap mass analyzer (Bruker Daltonics). Peptide mass fingerprint and sequence data were subjected to database search (SwissProt, Swiss Institute of Bioinformatics) using the Mascot search engine (Matrix Science LTD). A more detailed technical description is available in the online supplemental data.
Statistics
Results indicate mean±SEM. Multigroup comparisons were done by 1-way ANOVA followed by Student-Newman-Keuls posthoc all-pairwise testing using the SigmaStat 2.03 software, and P<0.05 was considered significant. 2D gel electrophoresis data were analyzed by ANOVA and Student t test using DeCyder Software (Amersham), and P<0.01 was considered significant.
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Results |
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Cardiac Hypertrophy and Hemodynamic Analysis
Cardiac mass and blood pressure were increased in ovx animals receiving chronic aldosterone infusion plus a high-salt diet (AST rats) compared with estrogen-depleted rats receiving a normal diet together with osmotic minipumps containing only carrier solution (Figure 1A and Table 1). Systolic and mean blood pressure levels, as well as relative heart weight, were lower in AST rats treated with the ER
agonist 16-LE2, the ERß agonist 8ß-VE2, or the nonselective ER agonist 17ß-estradiol compared with AST rats receiving placebo injections. Assessment of cardiac hypertrophy on the single cardiac myocyte level revealed a doubling of cardiac myocyte cross-sectional area in AST rats that was abrogated by treatment with the ER agonist 16-LE2, the ERß agonist 8ß-VE2, and the nonselective ER agonist 17ß-estradiol (Table 1 and Figure 1A and 1B).
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Global Measurements
Body mass was increased in ovariectomized compared with intact rats and not altered by aldosterone-salt treatment (Table 1). The selective ER agonist 16-LE2 and the nonselective ER agonist 17ß-estradiol but not the ERß agonist 8ß-VE2 attenuated the adipose phenotype of estrogen-depleted rats. Uterine weight and serum estradiol levels were decreased in ovx rats. Uterus atrophy was prevented by 17ß-estradiol and by 16-LE2 but not by the ERß agonist 8ß-VE2. Serum estradiol levels were lower in ovariectomized compared with sham-operated rats and returned to physiological levels in animals receiving injections with 17ß-estradiol. Serum angiotensin II levels were suppressed to a comparable extent among all of the animals receiving AST treatment (Table 1).
Vascular Remodeling and Gene Expression
Chronic aldosterone-salt treatment resulted in aortic media thickening (Figure 2A and 2B), perivascular fibrosis of coronary arteries (Figure 2C and 2D), and higher osteopontin expression levels in the aortic media compared with sham-operated rats or ovxs (Figure 2E and 2F). Treatment of AST rats with the ER agonist 16-LE2, the ERß agonist 8ß-VE2, or 17ß-estradiol attenuated aortic media hypertrophy, fibrosis, and osteopontin expression (Figure 2A through 2F). Cardiac ER and ERß protein expression and MR mRNA levels were not different among all of the treatment groups (see online supplemental data).
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Cardiac Proteome Analyses
On average, 
1400 individual protein spots were detected by 2D gel electrophoresis of unfractionated cardiac extracts (Figure 3A). Treatment of AST rats with the ER agonist 16-LE2, the ERß agonist 8ß-VE2, or the nonselective ER agonist 17ß-estradiol altered the expression levels of specific proteins involved in cardiac contractility (-myosin heavy chain [-MHC]), signal transduction (neurabin II), energy metabolism (ATP-synthase -chain), cellular stress response, and extracellular matrix formation (fibromodulin; Table 2 and Figure 3B), whereas lactate dehydrogenase-2, malate dehydrogenase, cardiac -actin, and reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase expression were not significantly responsive to estrogen treatment. Western blotting experiments confirmed the observation that 17ß-estradiol, 16-LE2, and 8ß-VE2 attenuated increased cardiac neurabin II expression in AST rats (see supplemental data).
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Discussion |
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The major findings of this study can be summarized as follows: First, activation of either ER
or of ERß protects female AST rats against hypertension, cardiac hypertrophy, vascular fibrosis, and increased osteopontin expression. Second, the efficacy of ER to modulate blood pressure varies substantially among different animal models. Third, aldosterone-salt treatment confers specific alterations on the cardiac proteome that are partially and differentially reversed by treatment with ER or ERß selective agonists.
Elevated aldosterone serum levels together with a high-salt diet promote hypertension and vascular dysfunction in humans and in animal models of human heart disease.9,21 Although ER and ERß augment local NO bioavailability, which is impaired by excess MR activation, hypertension has been reported only in ERß but not in ER knockout mice.11,15,16,20,22,23 Along the same line, the ER agonist 16-LE2 failed to decrease elevated blood pressure in spontaneously hypertensive rats.19 These findings could be taken as good evidence against a general function of ER in blood pressure maintenance. However, decreased blood pressure levels in AST rats receiving the ER agonist 16-LE2 are in contrast to such a general hypothesis. Instead, it seems that the functional role of ER in blood pressure maintenance presents differently in dependence of the cause or the model of hypertension. In particular, the suppression of angiotensin II levels in AST rats might confer a permissive effect on the ER agonist 16-LE2 to modulate blood pressure, because an identical dose of the same ligand failed to lower elevated blood pressure in female spontaneous hypertensive rats in which serum angiotensin II was much higher than in AST rats (P. Arias-Loza, unpublished data, 2006). Lower blood pressure levels among AST rats receiving the ERß agonist 8ß-VE2 are in direct line with elevated blood pressure in ERß knockout mice and provide novel and independent evidence in support of ERß as an important regulatory factor of blood pressure maintenance.23
Chronic aldosterone-salt treatment promoted extensive vascular remodeling in AST rats, which was linked to increased vascular osteopontin expression.11,21 Of note, osteopontin not only serves as a marker of vascular inflammation but also plays a functional role in vascular remodeling, because osteopontin-deficient mice are resistant to aldosterone-induced cardiac fibrosis.24 Interestingly, 17ß-estradiol has been shown to directly attenuate osteopontin expression in vascular smooth muscle cells.25 Together, these data suggest that the protective functions of 16-LE2, 8ß-VE2, and 17ß-estradiol on vascular remodeling and on vascular osteopontin expression are functionally linked processes.
Cardiac hypertrophy is a common consequence of hypertension and an independent predictor of cardiovascular mortality.26 Both ER subtypes have been reported to attenuate cardiac hypertrophy in genetic mouse models or in pharmacological studies.19,27,28 In contrast to previous studies in spontaneous hypertensive rats, which did not reveal a blood pressure–lowering effect of 16-LE2, the antihypertrophic effects of 16-LE2 (and of 8ß-VE2) in AST rats are most likely explained by lower blood pressure levels, though we cannot formally rule out the presence of additional and direct hormone effects on the myocardium. Smaller cardiac myocyte cross-sectional areas in AST rats receiving ER or ERß selective agonist treatment support this interpretation and indicate that beneficial estrogen effects can be achieved by an ERß ligand that does not stimulate uterine growth.
Although cardiac hypertrophy was attenuated by ER and ERß selective agonists, only the activation of ER by either 16-LE2 or by 17ß-estradiol and, of note, not the activation of ERß by 8ß-VE2, prevented the downregulation of cardiac -MHC expression in ovariectomized AST rats. These observations support the hypothesis that estrogens attenuate the downregulation of cardiac -MHC expression, which was repeatedly observed in estrogen-depleted rats via activation of the ER but not of the ERß receptor.19,29
In contrast to -MHC, activation of ER and of ERß attenuated increased expression levels of the scaffolding protein neurabin II, which targets protein phosphatase I to the actin cytoskeleton in AST rats.30,31 Enhanced cardiac protein phosphatase I targeting could be functionally relevant, because transgenic mice overexpressing protein phosphatase I develop a dilative cardiomyopathy-like syndrome.32
In contrast to -MHC and neurabin II, only by the ERß agonist 8ß-VE2 and 17ß-estradiol but, of note, not the ER agonist 16-LE2 prevented the downregulation of the ATP synthase -chain and of fibromodulin in AST rats. Fibromodulin expression and function have so far not been studied in the heart despite a single report showing increased expression of this protein in cardiac myxoma.33 Nevertheless, it is conceivable that fibromodulin might play a role in the maturation of the cardiac collagen matrix, because fibromodulin-deficient mice exhibit extreme tendon weakness and an excess of immature collagen fibrils resembling Ehlers-Danlos syndrome.34
Finally, a number of proteins involved in cardiac metabolism, stress response, and cellular and sarcomere structure, including lactate dehydrogenase-2, malate dehydrogenase, lactate dehydrogenase ß-chain, cardiac -actin, and reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase, showed differential expression patterns in AST rats that were not responsive to estrogen treatment and, hence, unlikely to affect the cardiac phenotype of estrogen-treated AST rats.
Perspectives
Clinical and experimental data suggest important interactions between mineralocorticoid and ER function in cardiac and vascular injury. This report shows that both ER subtypes possess redundant functions in protecting the cardiovascular system against the detrimental effects of aldosterone-salt treatment. Nonfeminizing ERß agonists have a therapeutic potential in treating hypertensive heart disease that deserves further evaluation.
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Acknowledgments |
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Sources of Funding
T.P. received support from the Interdisciplinary Center for Clinical Research "IZKF" Würzburg (Z4-70 and E83-N), P-A.A.-L. and V.J. received support from the German Academic Exchange Service (DAAD) and the IZKF Würzburg (P-A.A.-L.), and L.N. received support from the Medical Research Council (United Kingdom), the British Heart Foundation, and from the EUMORPHIA consortium (European Union framework program 5).
Disclosures
T.P. and L.N. have received financial support from the Schering AG Berlin that relates to the evaluation of novel steroid hormone receptor ligands. The remaining authors report no conflicts.
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Footnotes |
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Correspondence to Theo Pelzer, Medizinische Klinik I, University of Würzburg, Josef-Schneider Str 2, D-97080 Würzburg, Germany. E-mail pelzer_t@klinik.uni–wuerzburg.de
Received January 25, 2007; first decision February 14, 2007; accepted May 11, 2007.
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[Abstract/Free Full Text]
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