GPER–novel membrane oestrogen receptor

Zimmerman, Margaret A.; Budish, Rebecca A.; Kashyap, Shreya; Lindsey, Sarah H.

doi:10.1042/cs20160114

Cited by 95 publications

(60 citation statements)

References 161 publications

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“…In addition, beside ERs, G protein‐coupled estrogen receptor 1 (GPER), has emerged as a third ER. Despite conflicting results obtained with the different mice models of GPER inactivation,52 GPER activation has been reported to exert several beneficial effects in the cardiovascular system, including protection against atherosclerosis and hypertension 53, 54. Treatment with the selective agonist G‐1 reduces atherosclerosis in ovariectomized mice, and the beneficial effects of GPER in this model are associated with a reduction in macrophage and T‐cell recruitment, indicating an anti‐inflammatory mechanism 55.…”

Section: Discussionmentioning

confidence: 99%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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BackgroundAlthough estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane‐initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane‐initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization.Methods and ResultsUsing mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane‐initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow‐mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow‐mediated arteriolar remodeling.ConclusionsAltogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

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Section: Discussionmentioning

confidence: 99%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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“…Despite these examples of GPER-mediated cardioprotection, the exact roles of cardiac GPER could not be concluded, as the specificity of G1 binding to GPER is questionable [14]. The systemic administration of G1 or global GPER knockout also have effects on other tissues, which could influence whole body metabolism, blood pressure, endothelial function and inflammatory responses [15,18,33,34], ultimately interfering with myocardial structure and function. Compared to global GPER KO mice [32], this study demonstrated that GPER deletion specifically in cardiomyocytes impaired heart structure and functions not only in male, but also in female mice.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis

Wang

Sun

Chou

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Activation of G protein-coupled estrogen receptor (GPER) by its agonist, G1, protects the heart from stressors such as pressure-overload, ischemia, a high-salt diet, estrogen loss, and aging, in various male and female animal models. Due to nonspecific effects of G1, the exact functions of cardiac GPER cannot be concluded from studies using systemic G1 administration. Moreover, global knockdown of GPER affects glucose homeostasis, blood pressure, and many other cardiovascular-related systems, thereby confounding interpretation of its direct cardiac actions. We generated a cardiomyocyte-specific GPER knockout (KO) mouse model to specifically investigate the functions of GPER in cardiomyocytes. Compared to wild type mice, cardiomyocyte-specific GPER KO mice exhibited adverse alterations in cardiac structure and impaired systolic and diastolic function, as measured by echocardiography. Gene deletion effects on left ventricular dimensions were more profound in male KO mice compared to female KO mice. Analysis of DNA microarray data from isolated cardiomyocytes of wild type and KO mice revealed sex-based differences in gene expression profiles affecting multiple transcriptional networks. Gene Set Enrichment Analysis (GSEA) revealed that mitochondrial genes are enriched in GPER KO females, whereas inflammatory response genes are enriched in GPER KO males, compared to their wild type counterparts of the same sex. The cardiomyocyte-specific GPER KO mouse model provides us with a powerful tool to study the functions of GPER in cardiomyocytes. The gene expression profiles of the GPER KO mice provide foundational information for further study of the mechanisms underlying sex-specific cardioprotection by GPER.

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“…The hormone oestrogen acts through two classical oestrogen receptors (ER): ERα and ERβ. In addition, recent studies suggest that the G‐protein coupled ER may mediate some of the rapid actions of oestrogen in the vasculature (Zimmerman, Budish, Kashyap, & Lindsey, ). These receptors mediate the actions of steroid hormones through both genomic and rapid non‐genomic actions, which have been previously reviewed and are outside the scope of this review (Iorga et al, ; Mendelsohn & Karas, , ).…”

Section: The Effect Of Sex Hormones On Arterial Stiffnessmentioning

confidence: 99%

Sex differences in mechanisms of arterial stiffness

DuPont

Kenney

Patel

et al. 2019

British J Pharmacology

196

150

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Arterial stiffness progressively increases with aging and is an independent predictor of cardiovascular disease (CVD) risk. Evidence supports that there are sex differences in the time course of aging-related arterial stiffness and the associated CVD risk, which increases disproportionately in postmenopausal women. The association between arterial stiffness and mortality is almost twofold higher in women versus men. The differential clinical characteristics of the development of arterial stiffness between men and women indicate the involvement of sex-specific mechanisms. This review summarizes the current literature on sex differences in vascular stiffness induced by aging, obesity, hypertension, and sex-specific risk factors as well as the impact of hormonal status, diet, and exercise on vascular stiffness in males andfemales. An understanding of the mechanisms driving sex differences in vascular stiffness has the potential to identify novel sex-specific therapies to lessen CVD risk, the leading cause of death in males and females.Large conduit arteries are composed of three layers: (a) the outer tunica adventitia, (b) the middle tunica media, and (c) the inner tunica intima, each of which contributes to the overall stiffness of the vessel wall (Figure 1). The tunica adventitia consists primarily of fibroblasts,

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GPER–novel membrane oestrogen receptor

Cited by 95 publications

References 161 publications

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis

Sex differences in mechanisms of arterial stiffness

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