Published online before print March 21, 2005, doi: 10.1161/01.CIR.0000159262.18512.46
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(Circulation. 2005;111:1492-1498.)
© 2005 American Heart Association, Inc.
Heart Failure |
Increased Mortality and Aggravation of Heart Failure in Estrogen Receptor-ß Knockout Mice After Myocardial Infarction
From the Department of Medicine (T.P., P.-A.A.L., K.H., B.B., C.D., G.E.), University of Würzburg, Germany; San Raffaele Hospital (L.C.), University of Milan, Italy; Laboratory of Reproductive and Developmental Toxicology (J.F.C., K.S.K.), Research Triangle Park, NC; and University of Manchester (L.N.), Division of Cardiology, Manchester, United Kingdom.
Correspondence to Theo Pelzer, MD Department of Medicine, University of Würzburg, Josef-Schneider Straße 2, D-97080 Würzburg, Germany. E-mail pelzer_t{at}klinik.uni-wuerzburg.de
Received April 24, 2004; revision received November 20, 2004; accepted November 23, 2004.
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Abstract |
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Background— Lower mortality rates among women with chronic heart failure than among men may depend in part on the action of female sex hormones, especially estrogens. The biological effects of estrogens are mediated by 2 distinct estrogen receptor (ER) subtypes (ER
and ERß). The present study was undertaken to determine the role of ERß in the development of chronic heart failure after experimental myocardial infarction (MI). Methods and Results— Female ERß null mice (BERKOChapel Hill) and wild-type littermates (WT) were ovariectomized, given 17ß-estradiol, and subjected to chronic anterior MI (MI; BERKO n=31, WT n=30) or sham operation (sham; BERKO n=14, WT n=14). At 8 weeks after MI, both genotypes revealed left ventricular remodeling and impaired contractile function at similar average infarct size (BERKO-MI 32.9±5% versus WT-MI 33.0±4%); however, BERKO mice showed increased mortality (BERKO-MI 42% versus WT-MI 23%), increased body weight and fluid retention (P<0.01), higher ventricular pro-ANP expression (BERKO-MI 27.9-fold versus sham, WT-MI 5.2-fold versus sham; BERKO-MI versus WT-MI P<0.001), higher atrial natriuretic peptide serum levels, and increased phospholamban expression (P<0.05) compared with WT mice.
Conclusions— Systemic deletion of ERß in female mice increases mortality, aggravates clinical and biochemical markers of heart failure, and contributes to impaired expression of Ca2+-handling proteins in chronic heart failure after MI. Further studies are required to delineate the relative importance of cardiac and vascular effects of ERß and the role of ER in the development of heart failure.
Key Words: receptors • myocardial infarction • heart failure • hormones
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Introduction |
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Gender differences in cardiovascular disease have raised hope for preventive pharmacological approaches with natural estrogens.1 Disappointing results from controlled clinical end-point studies on the secondary prevention of coronary artery disease suggest that estrogen receptor signaling in the cardiovascular system is a complex process that at the present time is not understood sufficiently to develop preventive treatment strategies.2 Estrogen effects are mediated by 2 different nuclear hormone receptors, ER
and ERß, which are encoded by different genes and act as ligand-dependent transcription factors.3,4 Understanding the specific and physiological function of ER and ERß appears mandatory, because both receptors are expressed in cardiac myocytes, fibroblasts, and vascular cells, where they could exert either redundant, nonredundant, or even opposing biological effects.5–9 The specific function of both estrogen receptor subtypes has been studied extensively in the vascular system. From these studies, it appears that ER but not ERß is required for estrogens to inhibit neointima formation. In contrast, ERß plays an important role in the regulation of systemic blood pressure, because ERß but not ER knockout mice are moderately hypertensive.10–13 The nonselective ER and ERß agonist 17ß-estradiol attenuates cardiac hypertrophy, as we and others have shown, but the specific function of ER and ERß in heart muscle disease is less well understood.14–17 In the present study, we have tested the hypothesis that ERß attenuates the development of chronic heart failure after myocardial infarction (MI) in mice. If this hypothesis is accurate, deletion of ERß in mice would alter long-term mortality, aggravate clinical and biochemical markers of congestive heart failure, and eventually impair the expression of Ca2+-handling proteins after MI. |
Methods |
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Experimental Design
The study used homozygous ERß knockout mice (BERKO; ERß–/–) and wild-type littermates (WT; ERß+/+) generated by the laboratories of Korach, Smithies, and Gustafsson (BERKOChapel Hill).6 Heterozygous breeding pairs generated a total of 380 animals; homozygous female mice were identified by polymerase chain reaction genotyping of tail DNA.6 To achieve comparable estrogen serum levels among all treatment groups, all animals were ovariectomized and implanted with estradiol release pellets (0.3 mg E2 over 60 days of release time; Innovative Research of America) 1 week before MI; E2 pellets were renewed in week 6 after MI. MIs were generated in mice of 23 to 25 g body weight by placing a ligature around the left coronary artery as described previously under general anesthesia with isoflurane 1.5 vol% supplemented by 0.5l oxygen per minute (WT n=30; BERKO n=31); coronary ligature was omitted in sham-operated animals (WT n=14; BERKO n=14).18 Mice were closely monitored for clinical signs of heart failure until echocardiographic, hemodynamic, and molecular analyses, which were performed 8 weeks after MI; dead animals were retrieved for necropsy. All procedures were approved by the institutional animal research committee and performed in accordance with the animal care guidelines of the American Physiological Society.
Hemodynamic and Echocardiographic Measurements
Echocardiography was performed on a Toshiba Power Vision 6000 system with a 15-MHz ultrasound probe under general anesthesia with tribromoethanol/amylene hydrate (Avertin; 2.5% wt/vol, 6 µL/g body weight IP) under spontaneous respiration. 2D left-parasternal short-axis views at the level of the papillary muscles were recorded. Correct probe placement was judged by the round appearance of the left ventricular (LV) cavity after angulation and craniocaudal transducer movements. LV end-systolic and end-diastolic areas were calculated by manual tracings of the endocardial border followed by planimetry with the Nice software package (Toshiba Medical Systems). Simultaneous transversal M-mode tracings were recorded with the cursor placed in the middle of the LV cavity. Hemodynamic measurements were performed according to published protocols under light isoflurane anesthesia and spontaneous respiration (isoflurane 1.5 vol% supplemented by 0.5 L of oxygen per minute).19 LV pressure curves were recorded after catheter placement in the LV cavity; systolic and diastolic blood pressure measurements were obtained on catheter withdrawal in the thoracic aorta. All measurements were performed by a single trained investigator blinded to genotypes and treatment. Animals with small infarcts (<10% of LV circumference; BERKO n=6, WT n=8) and nonphysiological heart rates below 400 bpm (BERKO n=2, WT n=3) were excluded from morphometric, hemodynamic, echocardiographic, and molecular analyses.
Infarct Size
Animals were euthanized by injection of 1 mol/L KCl after hemodynamic measurements. The auricles and major vessels were removed, and the ventricles were cut in 3 sections that included apex, midventricle, and base. The midventricle was fixed in Tissue-TEC OCT and frozen at –80°C. Transverse cryosections (5 µm) from the region 1 mm below the ligature were stained with hematoxylin and eosin, Picosirius red, and Masson trichrome according to standard protocols. The inner and outer perimeters of the LV were traced with a digital imager system (Sigma Scan Pro). Infarct size was calculated independently from hematoxylin-and-eosin–, Picosirius red–, and Masson trichrome–stained sections as the percentage of infarcted LV versus total LV circumference. Values represent the average of 3 slides per animal.
Global Measurements
Body weight was measured in conscious mice before echocardiography and hemodynamic analysis; heart weight, lung weight, and uterus weight were measured after hemodynamic analysis. All animals were screened for ascites and pleural effusions; aspirates were subjected to routine biochemical analysis. Tibia length was measured on radiographic film.
Biochemical Measurements
Blood samples were obtained from the LV after hemodynamic analysis (800 µL average). Serum estradiol and atrial natriuretic peptide (ANP) levels were measured by radioimmunoassay (E2: estradiol-ultrasensitive radioimmunoassay, DSL; ANP:anti-1-28-ANF rat, Peninsula).
Western Blot Analysis
Western blot analysis of crude cardiac extracts generated from the base of the LV used the following antibodies: phospholamban (Alexis, 1:2000 mouse monoclonal), phospho-phospholamban (Upstate, 1:200 rabbit polyclonal), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a; Abcam, 1:1000 rabbit polyclonal), Na+/Ca2+-exchanger (Abcam, 1:200 mouse monoclonal), ANP (Chemicon, 1:1000 rabbit polyclonal), inducible nitric oxide synthase (iNOS; BD Transduction Laboratories, 1:200 mouse monoclonal), and endothelial nitric oxide synthase (eNOS; BD Transduction L, 1:200 mouse monoclonal). Crude extracts were subjected to SDS-PAGE gel electrophoresis and transferred onto nylon membranes before detection with the primary antibody and horse radish peroxidase–coupled secondary antibodies (Amersham) followed by enzyme-linked chemiluminescence detection. Identical extracts were used for analysis of the total amount of - and ß-myosin heavy chain (MHC) in SDS-PAGE, followed by protein silver staining (BioRad) as described previously.15 ImageQuant software (Biometra) was used for semiquantitative densitometric analysis based on peak area. GAPDH was used as internal standard (Chemicon, 1:3000 mouse monoclonal) in Western blots.
Statistical Analysis
Data are expressed as mean±SEM. Comparison of survival was performed from Kaplan-Meier plots followed by log-rank test. Multigroup comparisons were done by ANOVA tests followed by Student-Newman-Keuls post hoc pairwise testing. LV dP/dtmax was analyzed by 2-tailed Student t test. The incidence of ascites and pleural effusions was analyzed by Fisher exact tests. A probability value of <0.05 was considered significant in multiple testing of all measurements. SigmaStat 2.03 software (SPSS) was used for all tests.
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Results |
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Mortality
Mortality rates over the 8-week observation period were higher in ERß knockout mice with MI than in infarcted WT mice (BERKO-MI 42% versus WT-MI 23%; log-rank P=0.145), as shown in Figure 1. Postmortem necropsy verified the presence of MI in all infarcted animals, but signs of cardiac rupture occurred only in 2 mice (n=1 BERKO MI, n=1 WT MI) after MI. Deaths in sham-operated mice (n=1 BERKO sham, n=1 WT sham) occurred early after surgery and were related to postsurgical bleeding.
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Infarct Size
Extensive scarring within the infarct zone and compensatory cardiac hypertrophy were detected in both genotypes. Mean infarct size, calculated as percentage of LV circumference 8 weeks after MI, was not statistically different between BERKO mice and wild-type littermates before (not shown) and after exclusion of animals with either small MIs (measuring <10% of LV circumference) or nonphysiological heart rates (<400 bpm), as shown in Figure 2.
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Morphometry
In contrast to WT mice, body weight increased in BERKO mice after MI (Table; P<0.05), and body weight was significantly higher in BERKO than in wild-type mice after MI (BERKO-MI 29.2±0.9 g versus WT-MI 26.9±0.7 g; P<0.05). Pleural effusions and ascites were detected in BERKO mice but not in wild-type mice after MI. Biochemical and microbiological analysis of ascites and pleural effusions revealed sterile transudates with low total protein concentrations and low lactate dehydrogenase activity. Heart weight to tibia ratios, which were significantly higher in sham-operated BERKO mice than in WT mice, increased to a comparable level in both genotypes after MI. Accordingly, the absolute gain in cardiac mass was lower in BERKO mice (25.3%; P=NS) than in wild-type littermates (92.4%; P<0.05). Myocardial collagen content in the remote area increased in both genotypes to a comparable extent after MI (not shown). Lung weight and lung-to-body weight ratios increased substantially and to a comparable extent in infarcted mice of both genotypes. Uterine atrophy was not detected, and estradiol serum levels were within the range of estradiol levels normally observed during mouse estrus in all groups.
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Hemodynamic Analysis
Systolic blood pressure was slightly elevated in sham-operated BERKO mice compared with wild-type littermates (Table), but no differences in systolic blood pressure were detected in BERKO and WT mice after MI. Values for LV dP/dtmax and dP/dtmin were comparable among all sham-operated mice and decreased significantly in infarcted BERKO and WT mice. When compared directly, dP/dtmax was lower in BERKO than in WT mice after MI (WT-MI 6255±360 mm Hg/s versus BERKO-MI 5202±327 mm Hg/s; P<0.05; 2-tailed t test). LV end-diastolic pressure was moderately elevated in BERKO and WT mice after MI compared with sham-operated mice, and heart rates were comparable among all groups.
Echocardiographic Analysis
LV fractional shortening, end-diastolic dimensions, and end-systolic dimensions did not differ significantly between sham-operated BERKO and WT mice (Table). LV dilation and severe systolic dysfunction after MI were observed in both genotypes to a comparable extent as judged by increased end-diastolic and end-systolic dimensions and decreased LV fractional shortening.
LV Pro-ANP Expression and ANP Serum Levels
ANP serum levels, which were comparable in all sham-operated mice, increased significantly in BERKO mice after MI (BERKO-MI versus BERKO-sham, P<0.001; Figure 3). LV pro-ANP expression increased in both genotypes but to significantly higher levels in BERKO mice than in WT mice after MI (BERKO-MI versus WT-MI P<0.001). Linear regression analysis revealed a significant correlation between ANP serum levels and ventricular pro-ANP expression (r2=0.22, P<0.01), absolute heart weight (r2=0.28, P<0.05), and lung weight (r2=0.33, P<0.05).
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Cardiac Ca2+ Transporter and MHC Expression
MI resulted in comparable reexpression of ß-MHC in the LV of BERKO and WT mice (Figure 4A). SERCA2a expression was comparable among all treatment groups (Figure 4B). Total phospholamban expression was comparable between sham-operated BERKO and wild-type mice (Figure 4C). After MI, phospholamban expression increased significantly in BERKO mice but not in wild-type mice (BERKO-sham versus BERKO-MI P<0.05). Total phospholamban expression was higher in BERKO mice than in wild-type mice after MI (BERKO-MI versus WT-MI, P<0.05). The phosphorylation of phospholamban, which abolishes the inhibitory effect of phospholamban on SERCA2a function, decreased to a comparable extent in BERKO and wild-type mice after MI (Figure 4D). No significant differences in LV eNOS, iNOS, or Na+/Ca2+-exchanger expression were observed among the groups (data not shown).
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Discussion |
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The observations reported here support the hypothesis that ERß plays a relevant role in the development of heart failure, because BERKO mice showed increased mortality, fluid retention, and higher ventricular pro-ANP and phospholamban expression after chronic MI. Observational studies provided initial evidence for a protective effect of female gender and sex hormones in cardiovascular disease.1,20,21 Meanwhile, prospective end-point trials including the Heart and Estrogen/progestin Replacement Study (HERS) 1, HERS2, the Estrogen Replacement and Atherosclerosis Study (ERA), and the recently terminated Women’s Health Initiative study revealed controversial results on hormone replacement therapy with nonselective ER
and ERß agonists in human vascular disease.2,22–24 However, estrogen effects are not necessarily limited to vascular pathology, because estrogen effects on cardiac muscle represent another mechanism to explain gender differences in heart disease.14–16,25,26 Cardiac hypertrophy is attenuated by estrogens, but only a very limited number of studies have focused on estrogen effects in heart failure models, with partially conflicting results. Importantly, none of these studies assessed the specific role of ER or ERß, which can mediate redundant, divergent, or opposing functions in different target tissues.7,10,11,27 To determine the role of ERß in the development of chronic heart failure, we used ERß null mice and WT littermates. All animals were ovariectomized and given E2 to achieve constant and comparable estrogen serum levels in all groups instead of the fluctuating E2 serum levels that occur in intact mice with the estrus cycle. Infarct size is a crucial variable for the interpretation of results obtained from genetic or pharmacological animal models of heart failure after MI. Accordingly, increased long-term mortality in BERKO compared with wild-type mice might have resulted from larger infarct sizes in BERKO mice, which we could not rule out because postmortem quantification of infarct sizes was technically not feasible in most animals. Although it is conceivable that BERKO mice with the biggest MIs died and only BERKO mice with smaller MIs survived (mortality bias), mean infarct size was almost identical in surviving BERKO and WT animals. Although infarct size could only be measured in midventricular cross sections, to preserve tissue for molecular studies, aggravation of heart failure in surviving BERKO mice is unlikely to result from a different MI size but rather likely reflects a different systemic response toward a similar degree of cardiac injury, which most likely contributed to increased mortality in BERKO mice.
Only a limited number of studies so far have evaluated the role of estrogens in cardiac remodeling after MI. Smith et al28 reported detrimental effects of 17ß-estradiol during acute myocardial ischemia, followed by protective long-term effects such as decreased LV dilatation and wall tension in rats with chronic MI. Similarly, Cavasin et al29 reported on protective effects of estrogens on LV function in mice after MI. These reports contrast with data from Hugel et al17 and van Eickels et al,30 who observed either increased LV hypertrophy at comparable MI size or decreased MI size associated with increased LV remodeling and higher mortality in estrogen-treated mice or post-MI rats, respectively. Importantly, expression levels of ER and ERß and the functional role of specific ER subtypes has not been determined in most of these studies, although it is conceivable that both receptor subtypes might play different, similar, or opposing roles in the development of heart failure. Therefore, we determined the role of ERß in the development of chronic heart failure after experimental MI. The present results obtained in a loss-of-function model are compatible but do not prove the hypothesis that selective activation of ERß improves functional outcome after MI. However, they provide novel and testable hypotheses that can be tested in future studies with subtype-selective estrogen receptor ligands.
The development of heart failure after MI in humans and mice is linked to impaired LV contractility, ventricular remodeling (including LV dilatation and hypertrophy), and scaring of the remote and noninfarcted myocardium.31 On the basis of these criteria, extensive LV remodeling was present in BERKO and WT mice after MI. Although the present data provide no evidence for excess LV remodeling in BERKO mice, it is conceivable that lower LV contractile performance contributed to heart failure in ERß null mice. Impaired myocardial contractility in heart failure is closely linked to altered calcium homeostasis of cardiac myocytes. Therefore, we hypothesized that calcium transporter expression might be different in BERKO and WT mice after MI.32 Sarcoplasmatic calcium reuptake in diastole occurs predominantly via SERCA2a, which is inhibited by phospholamban in its nonphosphorylated state.33 SERCA2a inhibition by phospholamban consequently depletes sarcoplasmatic Ca2+ stores, which results in a net decrease of systolic calcium release via ryanodine receptors. Phospholamban levels increased substantially in BERKO but not in WT mice after MI. Increased phospholamban expression in BERKO mice together with unaltered SERCA2a expression and a comparable extent of phospholamban dephosphorylation in both genotypes predicts a net increase of SERCA2a inhibition in ERß nullizygous mice, which is known to decrease LV contractility.34 These findings are also consistent with decreased cardiac SERCA2a-to-phospholamban ratios reported by Ren and coworkers35 in estrogen-depleted rats and confirm functional links between estrogen receptor signaling and cardiac calcium homeostasis in cardiac muscle. We and others have shown that estradiol may also regulate cardiac contractility in rats via differential MHC expression; however -MHC and ß-MHC expression levels were similar in BERKO and WT mice after MI, and isomyosin expression is therefore unlikely to explain differences in myocardial contractility.15 Although ERß regulates vascular iNOS expression in mice, and despite increased mortality of iNOS knockout mice after MI, comparable cardiac iNOS expression levels among all study groups do not explain increased mortality and aggravation of heart failure in infarcted BERKO mice.36
Perspectives and Limitations
The present study used mice that harbor a systemic deletion of ERß, and some aspects of chronic heart failure in BERKO mice might thus be due to unopposed activity of ER. Further studies are therefore required to delineate whether deletion of ER causes similar or divergent effects in the development of heart failure. With the recent development of selective ER and ERß agonists, dissection of ER and ERß function is no longer limited exclusively to genetic mouse models but might also be assessed in pharmacological studies.37,38 Chronic heart failure is a clinical syndrome that involves multiple organ systems, and as stated previously, systemic factors are likely to contribute to worsening heart failure in BERKO mice after MI. However, systemic deletion of ERß in BERKO mice does not enable differentiation of cardiac from systemic effects of ERß. Thus, additional studies with conditional knockout systems will be required to delineate the relative importance of cardiac versus systemic ERß expression in the development of chronic heart failure.
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Acknowledgments |
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This study was supported in part by grants from the Interdisciplinary Center for Clinical Research Würzburg (IZKF, Dr Pelzer), the German Academic Research Foundation (DAAD, P. Arias-Loza), and the Medical Research Council (MRC, Dr Neyses).
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  C. J. Barrick, A. Dong, R. Waikel, D. Corn, F. Yang, D. W. Threadgill, and S. S. Smyth Parent-of-origin effects on cardiac response to pressure overload in mice Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H1003 - H1009. [Abstract] [Full Text] [PDF]
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V. Jazbutyte, P. A. Arias-Loza, K. Hu, J. Widder, V. Govindaraj, C. von Poser-Klein, J. Bauersachs, K.-H. Fritzemeier, C. Hegele-Hartung, L. Neyses, et al. Ligand-dependent activation of ER{beta} lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats Cardiovasc Res, March 1, 2008; 77(4): 774 - 781. [Abstract] [Full Text] [PDF]
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 D. Liu, A. Deschamps, K. S. Korach, and E. Murphy Estrogen-Enhanced Gene Expression of Lipoprotein Lipase in Heart Is Antagonized by Progesterone Endocrinology, February 1, 2008; 149(2): 711 - 716. [Abstract] [Full Text] [PDF]
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E. Murphy and C. Steenbergen Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury Cardiovasc Res, August 1, 2007; 75(3): 478 - 486. [Abstract] [Full Text] [PDF]
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C. F. Deschepper and B. Llamas Hypertensive Cardiac Remodeling in Males and Females: From the Bench to the Bedside Hypertension, March 1, 2007; 49(3): 401 - 407. [Full Text] [PDF]
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E. D. Lekgabe, S. G. Royce, T. D. Hewitson, M. L. K. Tang, C. Zhao, X. L. Moore, G. W. Tregear, R. A. D. Bathgate, X.-J. Du, and C. S. Samuel The Effects of Relaxin and Estrogen Deficiency on Collagen Deposition and Hypertrophy of Nonreproductive Organs Endocrinology, December 1, 2006; 147(12): 5575 - 5583. [Abstract] [Full Text] [PDF]
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B. Dawn and R. Bolli Increasing Evidence That Estrogen Is an Important Modulator of Bone Marrow-Mediated Cardiac Repair After Acute Infarction Circulation, November 21, 2006; 114(21): 2203 - 2205. [Full Text] [PDF]
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P. A. Arias-Loza, K. Hu, A. Schafer, J. Bauersachs, T. Quaschning, J. Galle, V. Jazbutyte, L. Neyses, G. Ertl, K.-H. Fritzemeier, et al. Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17{beta}-Estradiol in Aldosterone Salt-Treated Rats Hypertension, November 1, 2006; 48(5): 994 - 1001. [Abstract] [Full Text] [PDF]
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 Y.-C. Hsieh, M. A. Choudhry, H.-P. Yu, T. Shimizu, S. Yang, T. Suzuki, J. Chen, K. I. Bland, and I. H. Chaudry Inhibition of cardiac PGC-1{alpha} expression abolishes ER{beta} agonist-mediated cardioprotection following trauma-hemorrhage FASEB J, June 1, 2006; 20(8): 1109 - 1117. [Abstract] [Full Text] [PDF]
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Y.-C. Hsieh, S. Yang, M. A. Choudhry, H.-P. Yu, K. I. Bland, M. G. Schwacha, and I. H. Chaudry Flutamide restores cardiac function after trauma-hemorrhage via an estrogen-dependent pathway through upregulation of PGC-1 Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H416 - H423. [Abstract] [Full Text] [PDF]
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E. A. Booth, N. R. Obeid, and B. R. Lucchesi Activation of estrogen receptor-{alpha} protects the in vivo rabbit heart from ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2039 - H2047. [Abstract] [Full Text] [PDF]
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G. Schonfelder The biological impact of estrogens on gender differences in congestive heart failure Cardiovasc Res, September 1, 2005; 67(4): 573 - 574. [Full Text] [PDF]
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