The G-Protein-Coupled Estrogen Receptor Agonist Prevents Cardiac Lipid Accumulation by Stimulating Cardiac Peroxisome Proliferator-Activated Receptor α: A Preclinical Study in Ovariectomized-Diabetic Rat Model

Jafarynezhad, Faezeh; Shahbazian, Mohammad; Farhadi, Zeinab; Yadeghari, Maryam; Rezvani, Mohammad Ebrahim; Safari, Fatemeh; Azizian, Hossein

doi:10.5812/ijem-123560

Cited by 4 publications

(4 citation statements)

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“…In endothelial cells, oestrogen-mediated activation of GPER attenuates transcytosis of LDL cholesterol into endothelial cells, compatible with an indirect vasculoprotective effect 116 . G-1 also reduces cardiac lipid accumulation and PPARα expression in surgically postmenopausal rats with type 2 diabetes mellitus (T2DM) 117 . In human monocytes, which contribute to the earliest stages of atherogenesis 118 , the anti-inflammatory effects of oestrogen might involve both direct effects via GPER 119 as well as crosstalk between ERα and GPER 120 .…”

Section: Roles Of Gper In Physiology and Diseasementioning

confidence: 99%

The G protein-coupled oestrogen receptor GPER in health and disease: an update

Prossnitz

Barton

2023

Nat Rev Endocrinol

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Oestrogens and their receptors contribute broadly to physiology and diseases. In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.

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Section: Roles Of Gper In Physiology and Diseasementioning

confidence: 99%

The G protein-coupled oestrogen receptor GPER in health and disease: an update

Prossnitz

Barton

2023

Nat Rev Endocrinol

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“…Female rats were randomly assigned to five groups (7-10 rats in each group): Sham-Control (Sh-Ctl); T2D; Ovariectomized (OVX)+T2D; OVX+T2D+Vehicle (Veh); and OVX+T2D+G-1. Animals were OVX two weeks before the initiation of experiments as previously described [15]. To induce the T2D model, female rats were given a high-fat diet (HFD) for 8 weeks.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

“…The protective metabolic effects of E2 are traditionally attributed to classical E2 receptors, which are mediated by genomic pathways, a time-consuming and slow process [14]. Recently, increasing evidence has demonstrated that the G protein-coupled estrogen receptor (GPER), as a 7-transmembrane receptor is expressed in a wide variety of tissues such as the heart and blood vessels, and mediates the rapid biological action of E2 [15]. Based on genetic and pharmacological approaches, there is a growing body of literature emphasizing the role of GPER in the regulation of metabolic function of E2 as well as the regulation of cardiac function [12].…”

Section: Introductionmentioning

confidence: 99%

“…Based on genetic and pharmacological approaches, there is a growing body of literature emphasizing the role of GPER in the regulation of metabolic function of E2 as well as the regulation of cardiac function [12]. Recently, we and other authors demonstrated that E2 via GPER has metabolic cardiovascular and anti-inflammatory protective effects in postmenopause, T2D, and obesity [12,15]. However, the detailed mechanisms by which GPER can improve metabolic and cardiovascular disorders are not yet fully characterized [12].…”

Section: Introductionmentioning

confidence: 99%

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GPER activation attenuates cardiac dysfunction by upregulating the SIRT1/3-AMPK-UCP2 pathway in postmenopausal diabetic rats

Azizian,

Farhadi,

Bader

et al. 2023

PLoS ONE

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Postmenopausal diabetic women are at higher risk to develop cardiovascular diseases (CVD) compared with nondiabetic women. Alterations in cardiac cellular metabolism caused by changes in sirtuins are one of the main causes of CVD in postmenopausal diabetic women. Several studies have demonstrated the beneficial actions of the G protein-coupled estrogen receptor (GPER) in postmenopausal diabetic CVD. However, the molecular mechanisms by which GPER has a cardioprotective effect are still not well understood. In this study, we used an ovariectomized (OVX) type-two diabetic (T2D) rat model induced by high-fat diet/streptozotocin to investigate the effect of G-1 (GPER-agonist) on sirtuins, and their downstream pathways involved in regulation of cardiac metabolism and function. Animals were divided into five groups: Sham-Control, T2D, OVX+T2D, OVX+T2D+Vehicle, and OVX+T2D+G-1. G-1 was administrated for six weeks. At the end, hemodynamic factors were measured, and protein levels of sirtuins, AMP-activated protein kinase (AMPK), and uncoupling protein 2 (UCP2) were determined by Western blot analysis. In addition, cardiac levels of oxidative stress biomarkers were measured. The findings showed that T2D led to left ventricular dysfunction and signs of oxidative stress in the myocardium, which were accompanied by decreased protein levels of Sirt1/2/3/6, p-AMPK, and UCP2 in the heart. Moreover, the induction of the menopausal state exacerbated these changes. In contrast, treatment with G-1 ameliorated the hemodynamic changes associated with ovariectomy by increasing Sirt1/3, p-AMPK, UCP2, and improving oxidative status. The results provide evidence of the cardioprotective effects of GPER operating through Sirt1/3, p-AMPK, and UCP2, thereby improving cardiac function. Our results suggest that increasing Sirt1/3 levels may offer new therapeutic approaches for postmenopausal diabetic CVD.

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