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Estrogen receptor ? activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats.

ABSTRACT: AIMS:Little is known about the role of subcellular trafficking of estrogen receptor (ER) subtypes in the acute estrogen (E2)-mediated alleviation of oxidative stress. We tested the hypothesis that ER? migration to the cardiac myocyte membrane mediates the acute E2-dependent improvement of cellular redox status. MAIN METHODS:Myocardial distribution of subcellular ER?, ER? and G-protein coupled estrogen receptor (GPER) was determined in proestrus sham-operated (SO) and in ovariectomized (OVX) rats, acutely treated with E2 (1?g/kg) or a selective ER? (PPT), ER? (DPN) or GPER (G1) agonist (10?g/kg), by immunofluorescence and Western blot. We measured ROS and malondialdehyde (MDA) levels, and catalase and superoxide dismutase (SOD) activities to evaluate myocardial antioxidant/redox status. KEY FINDINGS:Compared with SO, OVX rats exhibited higher myocardial ROS and MDA levels, reduced catalase and SOD activities, along with diminished ER?, and enhanced ER? and GPER, localization at cardiomyocyte membrane. Acute E2 or an ER? (PPT), but not ER? (DPN) or GPER (G1), agonist reversed these responses in OVX rats and resulted in higher ER?/ER? and ER?/GPER ratios at the cardiomyocytes membrane. PPT or DPN enhanced myocardial Akt phosphorylation. We present the first evidence that preferential aggregation of ER? at the cardiomyocytes plasma membrane is ER?-dependent, and underlies E2-mediated reduction in oxidative stress, at least partly, via the enhancements of myocardial catalase and SOD activities in OVX rats. SIGNIFICANCE:The findings highlight ER? agonists as potential therapeutics for restoring the myocardial redox status following E2 depletion in postmenopausal women.

SUBMITTER: Steagall RJ

PROVIDER: S-EPMC5535783 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Estrogen receptor α activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats.

Steagall Rebecca J RJ Yao Fanrong F Shaikh Saame Raza SR Abdel-Rahman Abdel A AA

Life sciences 20170606

<h4>Aims</h4>Little is known about the role of subcellular trafficking of estrogen receptor (ER) subtypes in the acute estrogen (E<sub>2</sub>)-mediated alleviation of oxidative stress. We tested the hypothesis that ERα migration to the cardiac myocyte membrane mediates the acute E<sub>2</sub>-dependent improvement of cellular redox status.<h4>Main methods</h4>Myocardial distribution of subcellular ERα, ERβ and G-protein coupled estrogen receptor (GPER) was determined in proestrus sham-operated ...[more]

PMID: 28599865

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Project description:BACKGROUND:We documented the dependence of ethanol (EtOH)-evoked myocardial dysfunction on estrogen (E2 ), and our recent estrogen receptor (ER) blockade study, in proestrus rats, implicated ER? signaling in this phenomenon. However, a limitation of selective pharmacological loss-of-function approach is the potential contribution of the other 2 ERs to the observed effects because crosstalk exists between the 3 ERs. Here, we adopted a "regain"-of-function approach (using selective ER subtype agonists) to identify the ER subtype(s) required for unraveling the E2 -dependent myocardial oxidative stress/dysfunction caused by EtOH in conscious ovariectomized (OVX) rats. METHODS:OVX rats received a selective ER? (PPT), ER? (DPN), or GPER (G1) agonist (10 ?g/kg; i.v.) or vehicle 30 minutes before EtOH (1.0 g/kg; infused i.v. over 30 minutes) or saline, and the hemodynamic recording continued for additional 60 minutes. Thereafter, left ventricular tissue was collected for conducting ex vivo molecular/biochemical studies. RESULTS:EtOH had no hemodynamic effects in OVX rats, but reduced the left ventricular contractility index, dP/dtmax , and MAP after acute ER? (PPT) or ER? (DPN) activation. These responses were associated with increases in the phosphorylation of ERK1/2 and eNOS, and in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the myocardium. GPER activation (G1) only unraveled a modest EtOH-evoked hypotension and elevation in myocardial ROS. PPT enhanced catalase, DPN reduced ALDH2, while G1 had no effect on the activity of either enzyme, and none of the agonists influenced alcohol dehydrogenase or CYP2E1 activities in the myocardium. Blood EtOH concentration (96.0 mg/dl) was significantly reduced following ER? (59.8 mg/dl) or ER? (62.9 mg/dl), but not GPER (100.3 mg/dl), activation in EtOH-treated OVX rats. CONCLUSIONS:ER? and ER? play major roles in the E2 -dependent myocardial dysfunction caused by EtOH by promoting combined accumulation of cardiotoxic (ROS and MDA) and cardiodepressant (NOS-derived NO) molecules in female myocardium.

Project description:We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16-17 months of age. At 21-22 months of age rats began receiving daily injections of galanthamine (5mg/day) or vehicle. After one week, half of each group also received 17ß-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine+estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone was without significant effect. Effects were task-specific in that galanthamine+estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.

Project description:Introduction: Aging is accompanied by cardiovascular disorders which is associated with an imbalance of pro- and antioxidant systems, the mitochondrial dysfunction, etc. Glutathione (GSH) plays a critical role in protecting cells from oxidative damage. The aim of the work was to study the effect of exogenous glutathione on the redox status of mitochondria, the content of H2S and the function of the cardiovascular system in old rats. Methods: Experiments were performed on adult (6 months) and old (24 months) Wistar rats divided into three groups: adult, old and glutathionetreated old rats. Glutathione was injected intraperitoneally at a dose of 52 mg/kg. We investigated glutathione redox balance, H2S levels, oxidative stress, the opening of the mitochondrial permeability transition pore (mPTP), the resistance of isolated heart to ischemia/reperfusion in Langendorff model, endothelium-dependent vasorelaxation of isolated aortic rings, and cardiac levels of 3-MST, CSE, and UCP3 mRNA were determined using real-time PCR analysis. Results: Our data shows that in old rats treated with glutathione, the balance of its oxidized and reduced form changes in the direction of a significant increase (by 53.6%) of the reduced form. Glutathione pretreatment significantly increased the H2S levels, mtNOS activity, and UCP3 expression which considered as protective protein, and conversely, significantly decreased oxidative stress markers (the rate of O2•- generation, the levels of H2O2, diene conjugates and malone dialdehyde, in 2.5, 2.3, 2, and 1.6 times, respectively) in heart mitochondria. This was associated with the inhibition mitochondrial permeability transition pore opening and increased resistance of the isolated heart to ischemia/reperfusion in these animals. At the same time, in glutathione-treated old rats, we also observed restoration of endothelium-dependent vasorelaxation responses to acetylcholine, which were almost completely abolished by the NO-synthase inhibitor L-NAME. Conclusion: Thus, the pretreatment of old rats with glutathione restores the mitochondrial redox status and improves the function of the cardiovascular system.

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Estrogen receptor ? activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats.

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Estrogen receptor α activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats.

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