Estrogen Receptor Activation and Cardioprotection in Ischemia Reperfusion Injury

doi:10.1016/j.tcm.2010.05.001

Trends in Cardiovascular Medicine

Volume 20, Issue 3, April 2010, Pages 73-78

https://doi.org/10.1016/j.tcm.2010.05.001 Get rights and content

Premenopausal females have a comparably lower incidence of cardiovascular disease than their male counterparts. Although estrogen and activation of estrogen receptors (ERs) have been found to contribute to female protection, the complex mechanisms involved are unclear. Besides altering gene transcription, estrogen could elicit its cardioprotective effect via ER-mediated nongenomic signaling pathways. In addition to the two classic nuclear ER isoforms, ERα and ERβ, a G-protein coupled ER (GPR30 or GPER) has been found to be expressed in cardiomyocytes and plays an acute cardioprotective role in ischemia reperfusion injury. By using isoform-specific ER knockout mouse models and/or their specific modulators, the mechanisms of the different ERs involved in cardioprotection have been explored. In this review, we will focus on the signaling pathways leading to cardioprotection in ischemia reperfusion injury after ER activation and discuss the possibility and promise of specific ER modulators to treat ischemic heart diseases.

Section snippets

Isoform-Specific ER-Mediated Cardioprotection

Although epidemiologic studies have suggested that females have reduced cardiovascular disease, this protection is usually ascribed to the beneficial effects of estrogen on the lipid profile or on the vasculature (Vitale et al. 2009). A number of studies have suggested that acute addition of 17β-estradiol (E2) to either ovary-intact females or ovariectomized females reduces I/R injury (Booth et al., 2003, Hale et al., 1997). However, studies comparing I/R injury between males and females have

PI3K: A Common Cardioprotective Signaling Pathway by ER Activation?

In both in vivo and in vitro studies, Patten et al. (2004) have shown that acute E2 treatment reduces cardiomyocyte apoptosis and elicits cardioprotection via activation of PI3K/Akt signaling. Simoncini et al. (2000) have discovered a direct protein–protein interaction between ligand-activated ERα and the regulatory subunit p85 of PI3K in endothelial cells through a nongenomic mechanism by which E2 rapidly activates eNOS via the activation of PI3K/Akt. Thus, they speculate that ERα activation

Role of NO and Protein S-Nitrosylation in Cardioprotection in Females

Nitric oxide plays an important role in the regulation of cardiovascular function. In addition to the activation of cyclic guanosine monophosphate-dependent pathway, NO can regulate cell function through protein S-nitrosylation, a reversible, redox-sensitive posttranslational protein modification, which involves the attachment of an NO moiety to a nucleophilic protein sulfhydryl, resulting in S-nitrosothiol (SNO) formation. There are data suggesting an important role of protein S-nitrosylation

Conclusions and Future Perspective

Studies using isoform-specific ER modulators have shown that all ER subtypes, including ERα, ERβ, and GPR30, confer cardioprotective effects against I/R injury in both genomic and nongenomic mechanisms (Figure 1). As discussed above, the acute activation of each ER isoform causes the nongenomic activation of PI3K/Akt pathway (Deschamps and Murphy, 2009, Simoncini et al., 2000, Wang et al., 2009), which would lead to downstream activation of NOS/NO/SNO signaling (Chen et al., 1999, Lin et al.,

References (40)

ChungT.H. et al.
The interaction of estrogen receptor α and caveolin-3 regulates connexin43 phosphorylation in metabolic inhibition-treated rat cardiomyocytes
Int J Biochem Cell Biol
(2009)
GabelS.A. et al.
Estrogen receptor β mediates gender differences in ischemia/reperfusion injury
J Mol Cell Cardiol
(2005)
GrohéC. et al.
Cardiac myocytes and fibroblasts contain functional estrogen receptors
FEBS Lett
(1997)
NikolicI. et al.
Treatment with an estrogen receptor-beta-selective agonist is cardioprotective
J Mol Cell Cardiol
(2007)
NuedlingS. et al.
Activation of estrogen receptor β is a prerequisite for estrogen-dependent upregulation of nitric oxide synthases in neonatal rat cardiac myocytes
FEBS Lett
(2001)
RoperoA.B. et al.
Heart estrogen receptor alpha: distinct membrane and nuclear distribution patterns and regulation by estrogen
J Mol Cell Cardiol
(2006)
TerrellA.M. et al.
Postischemic infusion of 17-β-estradiol protects myocardial function and viability
J Surg Res
(2008)
VornehmN.D. et al.
Acute postischemic treatment with estrogen receptor-α agonist or estrogen receptor-β agonist improves myocardial recovery
Surgery
(2009)
WangM. et al.
Estrogen receptor β mediates acute myocardial protection following ischemia
Surgery
(2008)
AndersonG. et al.
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial
JAMA
(2004)

BabikerF.A. et al.

Oestrogen modulates cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms

Acta Physiol (Oxf)

(2007)

BoothE.A. et al.

Estrogen-mediated protection in myocardial ischemia-reperfusion injury

Cardiovasc Toxicol

(2008)

BoothE.A. et al.

17β-Estradiol as a receptor-mediated cardioprotective agent

J Pharmacol Exp Ther

(2003)

BoothE.A. et al.

Activation of estrogen receptor-α protects the in vivo rabbit heart from ischemia-reperfusion injury

Am J Physiol

(2005)

BopassaJ.C. et al.

A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury

Am J Physiol

(2010)

ChenZ. et al.

Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen

J Clin Invest

(1999)

DeschampsA.M. et al.

Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats

Am J Physiol

(2009)

FilardoE.J. et al.

Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF

Mol Endocrinol

(2000)

FiliceE. et al.

A new membrane G protein-coupled receptor (GPR30) is involved in the cardiac effects of 17beta-estradiol in the male rat

J Physiol Pharmacol

(2009)

HaleS. et al.

Estradiol, administrated acutely, protects ischemic myocardium in both female and male rabbits

J Cardiovasc Pharmacol Ther

(1997)

Cited by (126)

Aging, sex and NLRP3 inflammasome in cardiac ischaemic disease
2022, Vascular Pharmacology
Experimentally, many strong cardioprotective treatments have been identified in different animal models of acute ischaemia/reperfusion injury (IRI) and coronary artery disease (CAD). However, the translation of these cardioprotective therapies for the benefit of the patients into the clinical scenario has been very disappointing. The reasons for this lack are certainly multiple. Indeed, many confounding factors we must deal in clinical reality, such as aging, sex and inflammatory processes are neglected in many experiments. Due to the pivotal role of aging, sex and inflammation in determining cardiac ischaemic disease, in this review, we take into account age as a modifier of tolerance to IRI in the two sexes, dissecting aging and myocardial reperfusion injury mechanisms and the sex differences in tolerance to IRI. Then we focus on the role of the gut microbiota and the NLRP3 inflammasome in myocardial IRI and on the possibility to consider NLRP3 inflammasome as a potential target in the treatment of CAD in relationship with age and sex. Finally, we consider the cardioprotective mechanisms and cardioprotective treatments during aging in the two sexes.
Chronic GPER activation prevents ischemia/reperfusion injury in ovariectomized rats
2022, Biochimica et Biophysica Acta - General Subjects
During menopause women are exposed to an increase in cardiovascular risk. G protein-coupled estrogen receptor (GPER) is known to mediate several of the protective effects of such hormones. G1 was described as a selective and synthetic agonist for GPER. The aim of the present research is to evaluate the effect of a chronic treatment with G1 in ovariectomized (OVX) rats exposed to ischemia/reperfusion (I/R). Considering the hypothesis that an impaired mitochondrial state could be involved in the alterations produced in OVX rats, other objective of this study was to investigate it in an isolated preparation. Three months old rats were assigned to undergo either bilateral ovariectomy or sham operation. The OVX rats were randomly treated during one month with either G1 or vehicle. Cardiac mitochondria from OVX rats showed a depolarized membrane potential and a decreased calcium retention capacity in comparison with Sham rats, which were prevented by chronic G1 treatment. I/R caused a higher decrease of left ventricular developed pressure and a higher increase of left ventricular end diastolic pressure in OVX compared to Sham hearts. These altered mechanical parameters were prevented by G1. The induced infarct size was significantly higher in OVX, which was reduced by G1 treatment. These results indicate that the mitochondrial state in OVX rats is impaired, accompanied by an altered mechanical response after ischemia and reperfusion injury, which was effectively prevented with chronic treatment with G1. The present study may provide further insights for the potential development of a therapy based on the GPER modulation.
Ischemic heart disease and cardioprotection: Focus on estrogenic hormonal setting and microvascular health
2021, Vascular Pharmacology
Ischemic Heart Disease (IHD) is a clinical condition characterized by insufficient blood flow to the cardiac tissue, and the consequent inappropriate oxygen and nutrients supply and metabolic waste removal in the heart. In the last decade a broad scientific literature has underlined the distinct mechanism of onset and the peculiar progress of IHD between female and male patients, highlighting the estrogenic hormonal setting as a key factor of these sex-dependent divergences. In particular, estrogen-activated cardioprotective pathways exert a pivotal role for the microvascular health, and their impairment, both physiologically and pathologically driven, predispose to vascular dysfunctions. Aim of this review is to summarize the current knowledge on the estrogen receptors localization and function in the cardiovascular system, particularly focusing on sex-dependent differences in microvascular vs macrovascular dysfunction and on the experimental models that allowed the researchers to reach the current findings and sketching the leading estrogen-mediated cardioprotective mechanisms.
Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury
2021, JACC: Basic to Translational Science
Citation Excerpt :
First, to reduce sex-related variability, we only considered male C57Bl6/J mice. It has been reported that the estrogen-receptor ß has potential cardioprotective effects (32). Therefore, future I/R experiments in female mice are required.
The bacterial C-type lectin domain family 4 member E (CLEC4E) has an important role in sterile inflammation, but its role in myocardial repair is unknown. Using complementary approaches in porcine, murine, and human samples, we show that CLEC4E expression levels in the myocardium and in blood correlate with the extent of myocardial injury and left ventricular (LV) functional impairment. CLEC4E expression is markedly increased in the vasculature, cardiac myocytes, and infiltrating leukocytes in the ischemic heart. Loss of Clec4e signaling is associated with reduced acute cardiac injury, neutrophil infiltration, and infarct size. Reduced myocardial injury in Clec4e^–/– translates into significantly improved LV structural and functional remodeling at 4 weeks’ follow-up. The early transcriptome of LV tissue from Clec4e^–/– mice versus wild-type mice reveals significant upregulation of transcripts involved in myocardial metabolism, radical scavenging, angiogenesis, and extracellular matrix organization. Therefore, targeting CLEC4E in the early phase of ischemia-reperfusion injury is a promising therapeutic strategy to modulate myocardial inflammation and enhance repair after ischemia-reperfusion injury.
Flow-mediated outward arterial remodeling in aging
2021, Mechanisms of Ageing and Development
The present review focuses on the effect of aging on flow-mediated outward remodeling (FMR) via alterations in estrogen metabolism, oxidative stress and inflammation. In ischemic disorders, the ability of the vasculature to adapt or remodel determines the quality of the recovery. FMR, which has a key role in revascularization, is a complex phenomenon that recruits endothelial and smooth muscle cells as well as the immune system. FMR becomes progressively less with age as a result of an increase in inflammation and oxidative stress, in part of mitochondrial origin. The alteration in FMR is greater in older individuals with risk factors and thus the therapy cannot merely amount to exercise with or without a mild vasodilating drug. Interestingly, the reduction in FMR occurs later in females. Estrogen and its alpha receptor (ERα) play a key role in FMR through the control of dilatory pathways including the angiotensin II type 2 receptor, thus providing possible tools to activate FMR in older subjects although only experimental data is available. Indeed, the main issue is the reversibility of the vascular damage induced over time, and to date promoting prevention and limiting exposure to the risk factors remain the best options in this regard.
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.

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Review articlesEstrogen Receptor Activation and Cardioprotection in Ischemia Reperfusion Injury

Section snippets

Isoform-Specific ER-Mediated Cardioprotection

PI3K: A Common Cardioprotective Signaling Pathway by ER Activation?

Role of NO and Protein S-Nitrosylation in Cardioprotection in Females

Conclusions and Future Perspective

Int J Biochem Cell Biol

J Mol Cell Cardiol

FEBS Lett

J Mol Cell Cardiol

FEBS Lett

J Mol Cell Cardiol

J Surg Res

Surgery

Surgery

Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial

JAMA

Oestrogen modulates cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms

Acta Physiol (Oxf)

Estrogen-mediated protection in myocardial ischemia-reperfusion injury

Cardiovasc Toxicol

17β-Estradiol as a receptor-mediated cardioprotective agent

J Pharmacol Exp Ther

Activation of estrogen receptor-α protects the in vivo rabbit heart from ischemia-reperfusion injury

Am J Physiol

A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury

Am J Physiol

Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen

J Clin Invest

Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats

Am J Physiol

Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF

Mol Endocrinol

A new membrane G protein-coupled receptor (GPR30) is involved in the cardiac effects of 17beta-estradiol in the male rat

J Physiol Pharmacol

Estradiol, administrated acutely, protects ischemic myocardium in both female and male rabbits

J Cardiovasc Pharmacol Ther

Review articles
Estrogen Receptor Activation and Cardioprotection in Ischemia Reperfusion Injury