Theo Pelzer

The cardiovascular system of a premenopausal woman is prepared to adapt to the challenges of increased cardiac output and work load that accompany pregnancy. Thus, it is tempting to speculate whether enhanced adaptability of the female cardiovascular system might be advantageous under conditions that promote cardiovascular disease. In support of this concept, 17β-estradiol as the major female sex hormone has been shown to confer protective cardiovascular effects in experimental studies. Mechanistically, these have been partially linked to the prevention and protection against oxidative stress. Current evidence indicates that estrogens attenuate oxidative stress at two levels: first, by preventing generation of reactive oxygen species (ROS) and, second, by scavenging ROS in the myocardium and in the vasculature. The purpose of this review is to give an overview on current concepts on conditions and mechanisms by which estrogens protect the cardiovascular system against ROS-mediated cellular injury.

Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate estrogen receptors (ERs) ERα and ERβ. Because female sex hormones enhance global glucose use and because myocardial function and mass are tightly linked to cardiac glucose metabolism, we tested the hypothesis that expression and activation of the ERα might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Cardiac glucose uptake quantified in vivo by ¹⁸ F-fluorodeoxyglucose positron emission tomography was strongly impaired in ovariectomized compared with gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the nonselective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovariectomized mice. Cardiac ¹⁸ F-fluorodeoxyglucose uptake was strongly decreased in female ERα knockout mice compared with wild-type littermates. Analysis of cardiac mRNA accumulation by quantitative RT-PCR revealed an upregulation of genes involved in glycolisis and tricarboxylic acid cycle by ERα treatment. In conclusion, systemic activation of ERα is sufficient, and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardioprotective estrogen effects.

The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17β-estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI). To address this issue, we evaluated clinical signs of heart failure as well as left ventricular (LV) dysfunction and remodeling in ovariectomized rats subjected to chronic MI receiving E2 or E2 plus MPA. After eight weeks MI E2 showed no effects. Adding MPA to E2 aggravated LV remodeling and dysfunction as judged by increased heart weight, elevated myocyte cross-sectional areas, increased elevated left ventricle end diastolic pressure, and decreased LV fractional shortening. Impaired LV function in rats receiving MPA plus E2 was associated with increased cardiac reactive oxygen species generation and myocardial expression levels of NADPH oxidase subunits. These results support the interpretation that adding MPA to an E2 treatment complicates cardiovascular injury damage post-MI and therefore contributes to explain the adverse outcome of prospective clinical studies.

Elevated mineralocorticoid levels and female sex hormones have been shown to confer opposing effects on renal injury, but their combined effects are still unknown. Objective: Identify the function of estrogens and of different synthetic progestins on aldosterone salt–mediated renal disease. Methods: The role of 17β-estradiol, medroxyprogesterone acetate (MPA), and drospirenone during renal injury was studied in Wistar rats subjected to uni-nephrectomy plus aldosterone salt treatment. Results: Aldo-salt treatment of intact, ovariectomized, and estradiol-treated female rats resulted in remnant kidney hypertrophy without structural damage. Co-treatment with MPA, but not with drospirenone, increased kidney hypertrophy, fluid turnover, sodium retention, and potassium excretion. Medroxyprogesterone acetate also caused glomerular, vascular, tubular, and interstitial lesions that were accompanied by increased blood pressure and enhanced NADPH oxidase (p67phox) and sodium channel (α-ENaC) expression. Drospirenone, a progestin with anti-mineralocorticoid function, and spironolactone prevented kidney hypertrophy, hypertension, and sodium retention. Drospirenone and spironolactone also increased renal angiotensin II type 2 receptor expression and relieved aldosterone-induced suppression of serum angiotensin II levels. Conclusion: The choice of specific synthetic progestins has profound implications on the development of kidney injury and renal gene expression under conditions of elevated aldosterone serum levels and salt intake.

The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERα and ERβ, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ERα agonist 16α-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. 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 α-myosin heavy chain expression. Ligand-dependent activation of ERβ confers blood pressure lowering effects in SHR that are superior to those of 17β-estradiol or the ERα agonist 16α-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.

Objective: Cardiac mass increases with age and with declining estradiol serum levels in postmenopausal women. Although the non-selective estrogen receptor-α and -β agonist 17β-estradiol attenuates cardiac hypertrophy in animal models and in observational studies, it remains unknown whether activation of a specific estrogen receptor subtype (ERα or ERβ) might give similar or divergent results. Therefore, we analyzed myocardial hypertrophy as well as cardiac function and gene expression in ovariectomized, spontaneously hypertensive rats (SHR) treated with the subtype-selective ERα agonist 16α-LE2 or 17β-estradiol. Methods and Results: Long-term administration of 16α-LE2 or 17β-estradiol did not affect elevated blood pressure, but both agonists efficiently attenuated cardiac hypertrophy and increased cardiac output, left ventricular stroke volume, papillary muscle strip contractility, and cardiac α-myosin heavy chain expression. The observed effects of E2 and 16α-LE2 were abrogated by the ER antagonist ZM-182780. Improved left ventricular function upon 16α-LE2 treatment was also observed in cardiac MRI studies. In contrast to estradiol and 16α-LE2, tamoxifen inhibited cardiac hypertrophy but failed to increase α-myosin heavy chain expression and cardiac output. Conclusions: These results support the hypothesis that activation of ERα favorably affects cardiac hypertrophy, myocardial contractility, and gene expression in ovariectomized SHR. Further studies are required to determine whether activation ERβ mediates redundant or divergent effects.

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 (ERα and ERβ). The present study was undertaken to determine the role of ERβ in the development of chronic heart failure after experimental myocardial infarction (MI). Methods and Results— Female ERβ null mice (BERKO _{Chapel Hill} ) and wild-type littermates (WT) were ovariectomized, given 17β-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 P P Conclusions— Systemic deletion of ERβ in female mice increases mortality, aggravates clinical and biochemical markers of heart failure, and contributes to impaired expression of Ca ²⁺ -handling proteins in chronic heart failure after MI. Further studies are required to delineate the relative importance of cardiac and vascular effects of ERβ and the role of ERα in the development of heart failure.