Protection from Myocardial Reperfusion Injury by Acute Administration of 17β-Estradiol

doi:10.1006/jmcc.1996.0093

Journal of Molecular and Cellular Cardiology

Volume 28, Issue 5, May 1996, Pages 1001-1008

https://doi.org/10.1006/jmcc.1996.0093 Get rights and content

Abstract

Although several studies have demonstrated that chronic exposure to estrogen appears to be cardioprotective, acute circulatory effects of estrogen are largely unknown. Therefore, we studied the effects of acute administration of 17β-estradiol in myocardial ischemia/reperfusion. Cats were subjected to 90 min of left anterior descending coronary artery (LAD) occlusion and 270 min of reperfusion (MI/R). Either the estrogenic steroid, 17β-estradiol or its non-estrogenic isomer, 17α-estradiol was administered (i.v.) 30 min prior to reperfusion at 1μg/kg bolus followed by a constant infusion lasting the remaining duration of the protocol at 1μg/kg/h. Control cats were subjected to sham MI/R. Cats treated with 17β-estradiol demonstrated a marked reduction in cardiac necrosis following MI/R compared to cats receiving 17α-estradiol or phosphate buffered saline (17±2%v33±1% or 34±4% area of necrosis indexed to the area-at-risk,P<0.01). In addition, cats receiving 17β-estradiol exhibited reduced myocardial PMN infiltration in necrotic tissue as compared to 17α-estradiol treated cats. Moreover, 17β-estradiol administration attenuated neutrophil adherence toex vivocoronary vascular endothelium compared to the two controls (44±8 PMNs/mm²v79±7 PMNs/mm²or 86±7 PMNs/mm²P<0.01). These data indicate that 17β-estradiol protects against myocardial ischemia/reperfusion, in part, by attenuating PMN infiltration and subsequent injury due to PMN mediator release.

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Cited by (67)

An acute estrogen receptor agonist enhances protective effects of cardioplegia in hearts from aging male and female mice
2020, Experimental Gerontology
The G-protein coupled estrogen receptor (GPER) mediates rapid responses to estrogen. GPER activation may contribute to cardioprotective effects of estrogen in ischemia and reperfusion, although whether it is beneficial in aging myocardium is unclear. We determined whether a GPER agonist (G1) added to standard cardioplegic solution (used to protect hearts from ischemia-reperfusion injury during cardiac surgery) would improve outcomes in isolated hearts from adult and aged mice of both sexes.
Hearts from young adult (6–9 mos) and older (22–28 mos) mice were perfused with Krebs-Henseleit buffer for 15 min (37 °C) followed by cold (6–7 °C) St. Thomas'2 cardioplegia with G1 (0.5 μM), G1 (0.5 μM) plus G15 (GPER antagonist; 1 μM) or vehicle for 6 min. Hearts were then subjected to global ischemia (90 min; 23–24 °C) and reperfusion (30 min; 37 °C). Infarct size was quantified with triphenyltetrazolium chloride.
In adult females, left ventricular developed pressure (LVDP) recovered to only 45.1 ± 11.9% of baseline in control hearts in reperfusion, but recovered to 76.5 ± 3.9% with G1 treatment (p < 0.05) and this was blocked by G15. Similar results were obtained in older males and females (LVDP = 51.5 ± 10.6% vs. 84.8 ± 8.7% and 51.9 ± 5.5% vs. 90.0 ± 6.1% for older males and females, respectively; p < 0.05). By contrast, G1 had no effect on recovery of LVDP in hearts from adult males (26.6 ± 8.9% vs. 46.0 ± 14.2%). The rates of pressure development and decay showed a similar pattern of recovery in reperfusion. Infarcts were significantly smaller in G1-treated hearts from all older mice and in younger females, although G1 had no impact on infarct size in adult males (48.1 ± 7.7% for control vs. 32.6 ± 8.0% for G1).
G1 enhances cardioprotective properties of a standard cardioplegic solution in the aging myocardium of both sexes. Supplementation of cardioplegic solutions with GPER agonists is a potential translational intervention that may improve cardiac surgery outcomes in older adults.
Estrogen receptor subcellular localization and cardiometabolism
2018, Molecular Metabolism
In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ERα was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ERαAF-1 and ERαAF-2). However, besides these nuclear actions, a pool of ERα is localized in the vicinity of the plasma membrane, where it mediates rapid signaling effects called membrane-initiated steroid signals (MISS) that have been well described in vitro, especially in endothelial cells.
This review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ERα activation that contribute to the cardiometabolic protection conferred by estrogens. Indeed, new transgenic mouse models (affecting either DNA binding, activation functions or membrane localization), together with the use of novel pharmacological tools that electively activate membrane ERα effects recently allowed to begin to unravel the different modes of ERα signaling in vivo.
Altogether, available data demonstrate the prominent role of ERα nuclear effects, and, more specifically, of ERαAF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ERα signaling selectively mediates some of the estrogen endothelial/vascular effects (NO release, reendothelialization) and could also contribute to the regulation of energy balance, insulin sensitivity, and glucose metabolism. Such a dissection of ERα biological functions related to its subcellular localization will help to understand the mechanism of action of “old” ER modulators and to design new ones with an optimized benefit/risk profile.
Ischemic preconditioning: Interruption of various disorders
2017, Journal of the Saudi Heart Association
Citation Excerpt :
The incidence of coronary heart disease is relatively low among premenopausal women and increases sharply with the occurrence of menopause [130], which indicates that the female sex hormones, particularly estrogen, play a crucial role in reducing the risk of ischemic heart diseases [131,132]. Although animal models with surgical menopause (ovariectomy) indicate the cardioprotective effect of estrogen replacement [133,134], some clinical trials failed to demonstrate any cardioprotection from such estrogen replacement therapy [135,136]. In fact, the incidence of ischemic heart disease was increased in women receiving estrogen compared to those receiving placebo [136].
Ischemic heart diseases are the leading cause of morbidity and mortality worldwide. Reperfusion of an ischemic heart is necessary to regain the normal functioning of the heart. However, abrupt reperfusion of an ischemic heart elicits a cascade of adverse events that leads to injury of the myocardium, i.e., ischemia–reperfusion injury. An endogenous powerful strategy to protect the ischemic heart is ischemic preconditioning, in which the myocardium is subjected to short periods of sublethal ischemia and reperfusion before the prolonged ischemic insult. However, it should be noted that the cardioprotective effect of preconditioning is attenuated in some pathological conditions. The aim of this article is to review present knowledge on how menopause and some metabolic disorders such as diabetes and hyperlipidemia affect myocardial ischemic preconditioning and the mechanisms involved.
The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function
2011, Vascular Pharmacology
Endogenous estrogens are important regulators of cardiovascular homeostasis in premenopausal women and delay the development of hypertension and coronary artery disease. These hormones act via three different estrogen receptors affecting both gene transcription and rapid signaling pathways in a complex interplay. In addition to the classical estrogen receptors ERα and ERβ, which are known mediators of estrogen-dependent vascular effects, a G protein-coupled estrogen receptor termed GPER that is expressed in the cardiovascular system has recently been identified. Endogenous human 17β-estradiol, selective estrogen receptor modulators (SERMs) including tamoxifen and raloxifene, and selective estrogen receptor downregulators (SERDs) such as ICI 182,780 are all agonists of GPER, which has been implicated in the regulation of vasomotor tone and protection from myocardial ischemia/reperfusion injury. As a result, understanding the individual role of ERα, ERβ, and GPER in cardiovascular function has become increasingly complex. With accumulating evidence that GPER is responsible for a variety of beneficial cardiovascular effects of estrogens, this receptor may represent a novel target to develop effective strategies for the treatment of cardiovascular diseases by tissue-specific, selective activation of estrogen-dependent molecular pathways devoid of side effects seen with conventional hormone therapy.
Timing of the vascular actions of estrogens in experimental and human studies: Why protective early, and not when delayed?
2011, Maturitas
Citation Excerpt :
Whereas estrogen has been particularly well studied in animal and cell injury models of cerebral ischemia with nearly uniform favourable results, multiple cellular and molecular mechanisms at multiple sites could account for the beneficial estrogen's action in brain including: (1) decreased cell death; (2) increased neurogenesis; (3) enhancement of neurotrophic support; (4) suppression of pro-inflammatory pathways and (5) decrease of vessel permeability observed in the brain following estrogen treatment in rats. Furthermore, a number of epidemiological and animal studies have suggested a cardioprotective role of E2 on ischemia/reperfusion injury [57,58]. Cardiac ischemia/reperfusion elicits injuries not only to the myocardium, but also to the endothelium leading to the development of an early coronary endothelial dysfunction.
Estrogens, and in particular 17β-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes including the cardiovascular system. Although epidemiological studies and Nurses’ Health Study suggested, and all animal models of early atheroma clearly demonstrated a vasculoprotective action of both endogenous and exogenous estrogens, the Women's Health Initiative did not confirm the preventive action of estrogens against coronary heart disease (CHD). However, women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with increased CHD risk among women more distant from menopause. Thus, it is now mandatory to try to understand the mechanisms that could have influenced the actions of estrogens at various stages of atherosclerosis and/or of life. In this current review, we will summarize our understanding of the potential cellular targets and mechanisms of the vasculoprotective actions of estrogens, as well as of the lack of action of estrogens when administered after a period of hormonal deprivation. The mechanisms of the aggravating role of progestogens such as medroxyprogesterone acetate will be considered. Finally, we will analyze the possibilities to uncouple some beneficial from other undesirable actions following the partial/selective activation of estrogen receptors.
Females Exhibit Relative Resistance to Depressive Effects of Tumor Necrosis Factor-α on the Myocardium
2008, Journal of Surgical Research
Citation Excerpt :
Studies have consistently shown that females exhibit greater degree of cardioprotection, and much of this protection is attributed to estrogen and its receptors [5–7]. Acute [8] as well as chronic [9] administration of estrogen has been shown to provide protection from myocardial ischemia/reperfusion (I/R) injury. Conversely, there is evidence to suggest that endogenous testosterone exacerbates myocardial dysfunction following major trauma [10] and acute ischemic conditions [11], but the mechanisms by which testosterone contributes to cardiac dysfunction under such conditions are much less understood [5].
Tumor necrosis factor-alpha (TNF-α) plays a critical role in myocardial dysfunction following acute injury. It is unknown, however, if a gender-specific response to TNF infusion exists in isolated rat hearts. Elucidating such mechanisms is important to understanding the myocardial gender differences during acute injury. We hypothesize that females will exhibit a relative resistance to TNF-induced myocardial dysfunction compared to males and that menstrual cycle would influence the degree of female myocardial resistance to TNF-induced myocardial functional depression.
Adult male, proestrus female, and metestrus/diestrus female hearts were subjected to 60 min of TNF infusion at 10,000 pg/mL · min via Langendorff. Myocardial contractile function (left ventricular developed pressure, and the positive/negative first derivative of pressure) was continuously recorded.
10,000 pg/mL · min of TNF markedly depressed myocardial function in males compared with other doses of TNF. Myocardial function was significantly decreased in males compared to females following TNF infusion. Additionally, both the proestrus and the metestrus/diestrus females exhibited equal resistance to TNF-induced myocardial dysfunction.
Our study shows that females exhibit a significantly greater degree of resistance to TNF-induced myocardial depression. Moreover, data from this study suggest that fluctuations in estrogen during the reproductive cycle may have little to no influence on TNF-induced myocardial depression.

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^☆: Please address all correspondence to: Dr Allan M. Lefer, Department of Physiology, Jefferson Medical College, 1020 Locust St, Philadelphia, PA 19107, USA.

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Regular PaperProtection from Myocardial Reperfusion Injury by Acute Administration of 17β-Estradiol☆

Abstract

Regular Paper
Protection from Myocardial Reperfusion Injury by Acute Administration of 17β-Estradiol☆