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      The Role of Estrogen Receptors in Cardiovascular Disease

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          Abstract

          Cardiovascular Diseases (CVDs) are the leading cause of death globally. More than 17 million people die worldwide from CVD per year. There is considerable evidence suggesting that estrogen modulates cardiovascular physiology and function in both health and disease, and that it could potentially serve as a cardioprotective agent. The effects of estrogen on cardiovascular function are mediated by nuclear and membrane estrogen receptors (ERs), including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled ER (GPR30 or GPER). Receptor binding in turn confers pleiotropic effects through both genomic and non-genomic signaling to maintain cardiovascular homeostasis. Each ER has been implicated in multiple pre-clinical cardiovascular disease models. This review will discuss current reports on the underlying molecular mechanisms of the ERs in regulating vascular pathology, with a special emphasis on hypertension, pulmonary hypertension, and atherosclerosis, as well as in regulating cardiac pathology, with a particular emphasis on ischemia/reperfusion injury, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction.

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          The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

          Andrea Iorga, Christine M Cunningham, Shayan Moazeni … (2017)
          Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.
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            Ischemia/Reperfusion.

            Theodore Kalogeris, Christopher P. Baines, Maike Krenz … (2016)
            Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.
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              Estrogen receptor signaling mechanisms.

              Nathalie Fuentes, Patricia Silveyra (2019)
              The primary female sex hormones, estrogens, are responsible for the control of functions of the female reproductive system, as well as the development of secondary sexual characteristics that appear during puberty and sexual maturity. Estrogens exert their actions by binding to specific receptors, the estrogen receptors (ERs), which in turn activate transcriptional processes and/or signaling events that result in the control of gene expression. These actions can be mediated by direct binding of estrogen receptor complexes to specific sequences in gene promoters (genomic effects), or by mechanisms that do not involve direct binding to DNA (non-genomic effects). Whether acting via direct nuclear effects, indirect non-nuclear actions, or a combination of both, the effects of estrogens on gene expression are controlled by highly regulated complex mechanisms. In this chapter, we summarize the knowledge gained in the past 60years since the discovery of the estrogen receptors on the mechanisms governing estrogen-mediated gene expression. We provide an overview of estrogen biosynthesis, and we describe the main mechanisms by which the female sex hormone controls gene transcription in different tissues and cell types. Specifically, we address the molecular events governing regulation of gene expression via the nuclear estrogen receptors (ERα, and ERβ) and the membrane estrogen receptor (GPER1). We also describe mechanisms of cross-talk between signaling cascades activated by both nuclear and membrane estrogen receptors. Finally, we discuss natural compounds that are able to target specific estrogen receptors and their implications for human health and medical therapeutics.
              Article 0 comments Cited 214 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 17 June 2020
                Publication date Collection: June 2020
                Volume: 21
                Issue: 12
                Electronic Location Identifier: 4314
                Affiliations
                Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA; laryan@ 123456ucla.edu (L.A.); davidyounessi21@ 123456gmail.com (D.Y.); mikezargari@ 123456ucla.edu (M.Z.); SoBanerjee@ 123456mednet.ucla.edu (S.B.); JAgopian@ 123456mednet.ucla.edu (J.A.); Shadierahman@ 123456gmail.com (S.R.); RBorna@ 123456mednet.ucla.edu (R.B.); GRuffenach@ 123456mednet.ucla.edu (G.R.); SUmar@ 123456mednet.ucla.edu (S.U.)
                Author notes
                [* ]Correspondence: meghbali@ 123456ucla.edu
                Author information
                https://orcid.org/0000-0001-8036-3079
                https://orcid.org/0000-0002-6252-9976
                Article
                Publisher ID: ijms-21-04314
                DOI: 10.3390/ijms21124314
                PMC ID: 7352426
                PubMed ID: 32560398
                SO-VID: 879e0b09-a95f-426a-a8e0-92f5c494d0dc
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 24 May 2020
                Date accepted : 15 June 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: estrogen,estrogen receptors,estrogen receptor alpha,estrogen receptor beta,gpr30,hypertension,atherosclerosis,ischemia-reperfusion injury,heart failure with reduced ejection fraction,heart failure with preserved ejection fraction
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: estrogen, estrogen receptors, estrogen receptor alpha, estrogen receptor beta, gpr30, hypertension, atherosclerosis, ischemia-reperfusion injury, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction

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