Published online before print October 10, 2002, doi: 10.1161/01.ATV.0000041200.85946.4A
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© 2002 American Heart Association, Inc.
Brief Reviews |
Nonnuclear Actions of Estrogen
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass.
Correspondence to James K. Liao, MD, Vascular Medicine Research Unit, Brigham and Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu
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Abstract |
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Top
Abstract
IntroductionEstrogen has long been observed to endow cardiovascular protective effects, as evidenced by sex-specific differences in the incidence of hypertensive and coronary artery disease, the development of atherosclerosis, and myocardial remodeling after infarction. To exert its tissue-specific effects, the classic estrogen receptor (ER) functions as a ligand-dependent transcription factor. However, there is growing evidence that in response to 17ß-estradiol and heterologous signals, the ER can also mediate signaling cascades at the membrane and in the cytoplasm via various second messengers, such as receptor-mediated protein kinases. This review summarizes the current understanding of nonnuclear ER signaling and discusses the relevance to eliciting the beneficial cardiovascular effects of estrogen. These include vasodilation, inhibition of response to vessel injury, limiting myocardial injury after infarction, and attenuating cardiac hypertrophy. Defining the full repertoire of ER function promises to expose novel, highly specific targets for pharmacological interventions and may ultimately lead to the primary and secondary prevention of cardiovascular diseases.
Key Words: estrogen • estrogen receptors • transcription • vasculature • signaling
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Introduction |
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Sex-based differences in the incidence of hypertensive heart disease and coronary artery disease, the development of atherosclerosis, and cardiac remodeling after myocardial infarction have long been observed.1–3 In addition to improving risk factors, such as the lipid profile, estrogen also has direct effects on the myocardium, endothelium, and vascular smooth muscle. Although the estrogen receptor (ER) is classically a ligand-dependent transcription factor, it is becoming apparent that the receptor also modulates the activity of intracellular second messengers and membrane-associated receptors and signaling complexes, some of which can also enhance the classic activity of the ER. In the heart and vasculature, these nonnuclear signaling pathways mediate rapid vasodilation,4 inhibition of the response to vessel injury,5–10 reduction in myocardial injury after infarction,11,12 and attenuation of cardiac hypertrophy.13,14
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ER Structure and Function |
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The binding of 17ß-estradiol (E2) to the ER initiates a myriad of possible signal transduction pathways that, depending on the cellular context, elaborate responses as varied as survival, adhesion, and proliferation and culminate in physiological processes as divergent as cardiovascular protection, bone preservation, organogenesis, and cancer. The 2 subtypes of ER, ER
and ERß, are synthesized from separate genes and are structurally and functionally distinct. Both subtypes are classic steroid hormone receptors and are members of the nuclear receptor superfamily.15,16 The 5 steroid hormone receptors, constituting class I of the superfamily, share the same modular organization of a ligand-binding domain, DNA-binding domain, and 2 transcriptional activation function domains (Figure 1A). A central feature of classic ER action is ligand-dependent regulation of gene expression in target tissues.1,2,17 Binding of estrogen to ER releases the receptor from an inhibitory complex with heat shock proteins, leading to homodimerization and translocation of the receptor complex into the nucleus. The ER then binds to a 15-bp palindromic sequence called the estrogen response element (ERE), located in the promoter region of target genes. Maximum transcriptional activity requires the concerted actions of the ligand-independent activation function (AF)-1 domain (an area of site-specific phosphorylation) in the amino terminus and the ligand-dependent AF-2 in the carboxy terminus. Together, they recruit a coregulator complex to the promoter; the tissue, cell, and promoter-specific complex components expose the transcriptional template, resulting in transactivation or transrepression.18,19
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The cardiovascular importance of estrogen has been probed with receptor gene deletion or mutation studies20 (Figure 1B). A young man with a homozygous disruption in the ER gene resulting in the expression of a truncated receptor lacking DNA and hormone-binding domains developed premature coronary artery disease and impaired brachial endothelium-dependent vasodilation.21,22 However, this is only a single case study and should be viewed with caution because other genes may also be affected. Early studies in ovariectomized mice demonstrated that E2 inhibits intimal and medial vascular smooth muscle proliferation,9 suggesting a direct protective effect of estrogen on endothelial and vascular smooth muscle cells (VSMCs). In subsequent carotid injury studies, E2 inhibited medial thickening and VSMC proliferation in wild-type and ER knockout (ERKO) mice,23 implying that the protective effect of E2 could be mediated in an ER-independent manner. Furthermore, in ER and ERß double-knockout mice, E2 inhibited only VSMC proliferation, suggesting instead that a retained splice variant of ER that lacked only the amino-terminal activation function domain could mediate partial protection.24,25 This quandary was resolved with the production of complete ER null mice, which exhibit increased medial area, VSMC proliferation, and deposition of proteoglycans in response to vascular injury.26,27 Similarly, hearts from ERKO mice subjected to global ischemia and reperfusion exhibit greater global ischemia and a higher incidence of arrhythmias.28 Hearts from ERKO mice also have higher calcium accumulation, implying that E2 inhibits calcium influx and attenuates the harmful effects of calcium overload during myocardial ischemia/reperfusion. The mechanism of these effects may involve NO, which ameliorates coronary dysfunction and reduces tissue edema by decreasing microvascular permeability, inasmuch as hearts from ERKO mice demonstrate decreased NO release. ER also mediates the neuroprotective effects of E2 after cerebral ischemia, as demonstrated by greater stroke sizes in ovariectomized ERKO mice subjected to permanent cerebral ischemia.29
In addition, there is growing evidence that ERß may also have an important function in the vasculature.30 ERß expression is induced in VSMCs after vascular injury,31 and ERß knockout mice exhibit hypertension and ion channel dysfunction in VSMCs.32
This review, however, will focus on ER, given the greater body of work available. Discerning the components of the rapidly expanding ER signaling network and understanding its potential role in disease states may provide new opportunities for highly context-specific therapeutic strategies.
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Nonnuclear Actions of Estrogen |
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Our appreciation of the potency and versatility of ER
signaling is growing in light of accumulating evidence that ER can also elicit rapid cellular effects that peak minutes after stimulation in multiple cell types (Figures 2 and 3). Given that the rapidity of activation makes modulation of gene transcription less likely and that the effects are not blocked by inhibitors of protein or RNA synthesis, these extranuclear mechanisms are commonly referred to as "nonnuclear" or "nongenomic" effects of estrogen. These signaling cascades recruit second messengers including calcium and NO, receptor tyrosine kinases including epidermal growth factor (EGF) receptor and insulin-like growth factor (IGF)-1 receptor, G-protein–coupled receptors (GPCRs), and protein kinases including phosphoinositide-3 kinase (PI3K), serine-threonine kinase Akt, mitogen-activated protein kinase (MAPK) family members, nonreceptor tyrosine kinase Src, and protein kinases A and C (see reviews17,33–42; Figure 2).
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Because many of these estrogen-stimulated pathways are typically initiated at the plasma membrane, many investigators have sought to determine the existence of a membrane-associated ER. Indeed, membrane binding sites for E2 were first implicated in 1977, but the precise nature of the receptor remains elusive.43 Examination of the structure of ER further increases the controversy surrounding the existence of a membrane receptor. For example, ER possesses neither intrinsic kinase nor phosphatase activity, does not have hydrophobic stretches that could represent transmembrane domains, and lacks myristoylation and palmitoylation sequences that could anchor it to the membrane. To date, indirect evidence of a membrane ER comes from immunohistochemistry and from studies with membrane-impermeable ligands44–49 or overexpressed nuclear receptors.50
Studies with E2, which has been conjugated to BSA34,51–53 or to fluorescent macrocomplexes,54,55 suggest that a small population of cellular ER may be localized to the cellular membrane, inasmuch as both membrane-impermeable forms elicit the same rapid effects as unconjugated E2. Although contamination with unlabeled ligand is a possible confounding factor, E2-BSA competes with unlabeled E2, tamoxifen, and ER antibody for binding to the cell membrane and enters the cytoplasm only when the cells are permeabilized.55 E2-BSA also does not activate ERE-dependent transcription, again suggesting that the compound remains extracellular.52,53 Finally, the nonnuclear cascades observed with E2-BSA stimulation are not inhibited with the intracellular pure ER antagonist ICI 182,780.52 Of particular relevance to the vascular system is the observation of a membrane receptor in endothelial cells (ECs) that binds either E2 or E2-BSA rapidly and selectively activates antiapoptotic p38ß MAPK and inhibits proapoptotic p38, leading to upregulation of MAPK-activated protein kinase-2 kinase and phosphorylation of heat shock protein hsp27.56 Downstream effects of these effects include preservation of stress fiber formation and membrane integrity, prevention of hypoxia-induced apoptosis, and induction of both EC migration and the formation of primitive capillary tubes. Thus, estrogen may exploit pathways that preserve the actin cytoskeleton during ischemia, prevent cell death, and enhance angiogenesis after injury. However, parallel studies in cultured ERKO cells are needed to confirm the role of ER. Furthermore, vascular endothelial growth factor uses cross talk between PI3K-Akt pathways to inhibit p38 MAPK apoptotic pathways in ECs.57 Whether ER also uses this mechanism to differentially activate the and ß isoforms of p38 MAPK remains to be determined.
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Signaling Cascades Downstream From ER |
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Nonnuclear activation of the PI3K-Akt signaling cascade has been observed in neuronal and vascular systems.58–60 In rat primary cortical neurons, ER
mediates protection from glutamate-induced toxicity, a model for Alzheimer’s disease, via PI3K and Akt.58 In the vasculature, short-term exposure to E2 leads to vasodilation via NO-dependent pathways.61 In healthy blood vessels, the secretion of NO, which relaxes smooth muscle cells and inhibits platelet activation via a cGMP-dependent mechanism, is vasculoprotective. In cultured ECs, estrogen enhances NO release within minutes without altering the expression of endothelial NO synthase (eNOS).59,60,62,63 The enhancement in eNOS activity occurs in a biphasic manner through MAPK and PI3K-Akt pathways. This leads to enhanced NO release, which mediates vasodilation and decreases leukocyte adhesion in vessels subjected to ischemia/reperfusion injury.60 A similar mechanism has also been implicated in myocardial protection by high-dose corticosteroids during ischemia/reperfusion injury.64 Furthermore, in the vascular and cardiac protection model systems, ER and the glucocorticoid receptor activate PI3K activity by association with the p85 regulatory subunit of PI3K in a ligand-dependent manner.60 Alternatively, rapid E2-mediated vasorelaxation may occur in an endothelium-independent manner by changes in calcium flux in VSMCs.65
The presence of chaperone hsp90 upregulates eNOS activity in ECs,66 and hsp90 inhibitors disrupt the E2-induced hsp90-eNOS association.67 Indeed, the hsp90 inhibitor geldanamycin, the PI3K inhibitor LY294002, and the eNOS inhibitor N
-nitro-L-arginine methyl ester inhibit E2-dependent vasodilation of rat aortic rings.68 Because hsp90 interacts with eNOS and Akt and modulates eNOS activity, hsp90 likely functions as a scaffold to regulate Akt-dependent phosphorylation of eNOS.69
Nonnuclear recruitment of MAPK signaling cascades by ER has also been demonstrated. Activation by estrogen of extracellular signal–regulated kinase (ERK)-1/2 has been shown in cardiomyocytes,70 colon cancer,71 breast cancer,72 and bone,73,74 leading to responses that include cell growth, cell cycle progression, and survival. The antiproliferative effects of estrogen in VSMCs75 and lung myofibroblasts,76 on the other hand, are mediated by inhibition of ERK-1/2. Interestingly, by activating MAPKs in a nonnuclear manner, ER may be amplifying its classic function as a transcription factor. For instance, E2 rapidly activates ERK-1/2 in lactotroph cells; this activation upregulates prolactin gene transcription, a mechanism of activity that occurs in parallel with direct ER activation of the prolactin gene by classic ERE-dependent transcriptional activation.77 Nonnuclear ER activity can also give rise to ERE-independent transcriptional activation. In human neuroblastoma cells, E2-BSA induces the transcription of a reporter gene construct driven by the promoter of the immediate-early gene c-fos.52 In addition, E2 rapidly increases the expression of early growth response gene-1 in cardiac myocytes by inducing the recruitment of serum response factor to serum response elements in the early growth response gene-1 promoter via ERK-1/2.78
Rapid activation of more proximal kinases may be the mechanism for the activation of ERK by estrogen. In overexpression systems, the liganded ER induces rapid phosphorylation of the IGF-1 receptor and activation of ERK-1/2. Indeed, the 2 receptors coimmunoprecipitate in a ligand-dependent manner, suggesting a direct physical interaction between ER and the IGF-1 receptor.79 In breast cancer cell lines, ER induces rapid phosphorylation of the adaptor proteins, Src and Shc, in a ligand-dependent manner, resulting in an Shc–growth factor receptor binding protein (Grb)-2–son of sevenless (SoS) complex formation.80 This leads to the subsequent activation of Ras, Raf, and MAPK. Similarly, in breast and prostate cancer cells, E2 treatment activates the Src-Ras-ERK pathway, leading to cell cycle progression.81,82 In these studies, direct interaction between phospho-Tyr537 of ER and the Src homology domain 2 activates Src activity. In cortical neurons subjected to glutamate toxicity, estrogen also rapidly activates Src family tyrosine kinases and tyrosine phosphorylation of Ras, leading to neuroprotection.83 Furthermore, rapid phosphorylation of Src has also been observed in osteoclasts, although the ramifications for bone resorption remain to be defined.84 Interestingly, in osteoblasts, osteocytes, and embryonic fibroblasts, activation of an Src-Shc-ERK signaling pathway prevents apoptosis.85 Finally, in breast cancer cells, Src modulates PI3K-Akt signaling by a reversible cross-talk mechanism in which ligand binding induces the formation of a ternary complex between ER, PI3K, and Src.86 Cross talk between PI3K and Src has also been observed in osteoclasts87 and bone marrow cells.88 Whether a similar complex plays a role in eNOS activation in ECs remains to be determined.
In addition to recruiting ERK-1/2, ER also modulates other MAPK family members. ER in the heart selectively activates MAPK cascades to modulate the development of cardiac hypertrophy.13,14,89 For example, mice were protected from pressure-overload hypertrophy by ER-mediated selective inhibition of p38 MAPK.90 Apparently, ERK and c-Jun N-terminal kinase (JNK) are not involved,90 consistent with recruitment of p38 in other models of cardiac hypertrophy.91,92 In breast cancer cells stably transfected with ER and resistant to the anti-estrogen tamoxifen, loss of estrogen-mediated activation of p38 MAPK is correlated with survival.93 In ER-positive breast cancer cell lines, however, activation of JNK promotes survival from taxol-induced or ultraviolet radiation–induced apoptosis.53 Finally, induction of eNOS and inducible NOS in cardiac myocytes is blocked by the MAPK inhibitor PD98059,70 which may have clinical relevance because NO inhibits caspase activation and prevents the development of congestive heart failure.94
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E2-Independent Nonnuclear Activity Potentiates AF-1 Function |
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The nonnuclear ER
activity has been shown to enhance the nuclear activity of the receptor in the context of E2-independent activation of the receptor. Indeed, ER integrates a variety of heterologous signals, including dopamine,95,96 serum,97 cAMP,98 caveolin,99,100 and cyclins A and D.101–104 Activation by EGF and IGF-1 provides the best example of modulation of ER nuclear activity by nonnuclear E2-independent stimulation. Through this cross-talk mechanism, mitogenic extracellular signals are translated into cell cycle progression or, in cancer cells, into proliferation in the absence of hormone.105 EGF-stimulated and IGF-1–mediated stimulation of MAPKs results in the direct phosphorylation of ER on Ser118.73,106,107 Phosphorylation of ER enhances the binding of p68 RNA helicase108 and accounts for enhanced AF-1 transcriptional activity in uterine and ovarian adenocarcinoma cells.109–111
In addition to direct phosphorylation of the receptor, EGF can also modulate the coactivator phosphorylation state. Steroid receptor coactivator-1, a member of the p160 family of adaptor molecules that recruit other proteins to the coactivator complex, contains consensus sequences for ERK-1/2, and EGF stimulation results in ERK-1/2–mediated phosphorylation of steroid receptor coactivator-1, which potentiates ER transcriptional activity.112 Alternatively, EGF or IGF-1 stimulation can activate the PI3K-Akt pathway, which in turn, activates E2-responsive target genes. In breast cancer cell lines, EGF or IGF-1 treatment cause rapid phosphorylation and activation of Akt, leading to increased levels of progesterone receptor mRNA and protein.113 All of these effects were blocked by the PI3K inhibitor, wortmannin, and ICI 182,780 and were mimicked in the presence of a constitutively active Akt mutant. Akt may also activate ER by phosphorylation of Ser167 within the AF-1 domain.113 Interestingly, ER binds constitutively to the p85 subunit of PI3K and activates PI3K/Akt in an E2-independent manner, implicating a feed-forward mechanism of ER activation.114
Finally, nonreceptor tyrosine kinase Src, in addition to modulating E2-dependent nonnuclear activities of ER in the setting of mitogen and PI3K stimulation, may influence the transcriptional activity of ER in an E2-independent manner. In cells overexpressing ER and v-Src, Src stimulates ER transcriptional activity by enhancing AF-1 function via 2 parallel cascades. In the first instance, an Src–Raf-1–mitogen-activated ERK kinase–ERK pathway leads to phosphorylation of Ser118 in the AF-1 domain.115 In the same cells, a second pathway mediated by Src, mitogen-activated ERK kinase kinase, JNK kinase, and JNK may indirectly activate transcription by modulating AF-1–associated coactivators.115 Although these studies have implications for the role of Src in tumor progression, it is also interesting to speculate whether there could be a feedback mechanism by which nonnuclear activation of Src by ER enhances ER transcriptional activity.
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Membrane Origin of Nonnuclear ER Activity |
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The trafficking of ER
to different cellular compartments may be regulated by the nature of stimulation. In VSMCs transfected with ER, MAPK activation mediates nuclear translocation of ER from the membrane by E2-dependent and -independent mechanisms.116 Another proposed mechanism for membrane-initiated signaling by ER involves receptor association with membrane caveolae, which are cholesterol-rich membrane domains containing signaling molecules such as G proteins, GPCRs, PKC, receptor tyrosine kinases (RTKs), and non-RTKs. In fractionated EC plasma membranes, ER protein has been localized to caveolae, and E2 stimulates eNOS in isolated caveolae in an ER- and calcium-dependent manner.117–119 The close association of ER with caveolae and the regulation of eNOS phosphorylation and activity with hsp90 suggest an additional mechanism of action, inasmuch as caveolin-1 (cav-1), the coat protein for caveolae, and hsp90 independently coimmunoprecipitate with eNOS in EC lysates.120 Indeed, hsp90–eNOS–cav-1 may exist in a heterotrimeric complex in ECs such that the cav-1 scaffolding peptide is inhibitory and, on increase in cytoplasmic calcium, calcium-activated calmodulin may aid in the further recruitment of hsp90 to the complex by facilitating the release of the caveolin from eNOS.120,121 In vivo confirmation has been obtained by systemic administration of a chimeric peptide containing the cav-1 scaffolding peptide to mice. The protein was taken up by ECs and suppressed NO production and acute inflammation.122
Nonnuclear ER signaling also involves membrane heterotrimeric G proteins. For example, in Chinese hamster ovary cells transfected with ER cDNA, membrane and nuclear-localized receptors are detected.50 ER in the membrane fractions activated Gq and Gs and rapidly stimulated inositol phosphate production and adenylyl cyclase activity, respectively. Alternatively, G-protein activation has also been shown in ECs, where E2 activation of eNOS can be inhibited with ICI 182,780, RGS-4 (a regulator of G-protein signaling specific for Gi and Gq), and pertussis toxin (specific for Gi). In coimmunoprecipitation studies, ER interacted with Gi but not Gq or Gs in a ligand-dependent manner, whereas pertussis toxin completely blocked this interaction.123
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Are There Other ER Isoforms? |
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Nonnuclear signaling alternatively requires a GPCR that is distinct from ER
. Indeed, in macrophage cell lines, E2 and E2-BSA induced a rise in intracellular calcium that was inhibitable with pertussis toxin, and sequestration of a E2-GPCR occurred independently of clathrin-caveolin pathways.124,125 An E2-GPCR has also been postulated to exist in the hippocampus, where E2 stimulation potentiates kainate-induced currents through the modulation of protein kinase A activity.126
Recent evidence suggest that the nonnuclear effects of estrogen are, in fact, mediated by a receptor distinct from ER or ERß. For example, in the cerebral cortex, estrogen rapidly stimulates tyrosine phosphorylation of c-Src, which then induces phosphorylation of Shc and Shc–growth factor receptor binding protein-2 complex formation,127 which is upstream from ERK and B-Raf activation.128 Coincidentally, hsp90 coimmunoprecipitates with ERK-1/2 and may either preserve its conformation for subsequent phosphorylation with mitogen activated ERK kinase-2 or protect the phosphorylated kinase from phosphatases.129 Surprisingly, however, the pathway is intact and not inhibitable by ICI 182,780 in ERKO cortical explants, and ER- and ERß-selective ligands fail to reproduce the effects in KO cells. Taken together, these data suggest that a novel receptor, responsive to E2 but insensitive to ICI, mediates nonnuclear neurite differentiation.
There is considerable controversy regarding the nature of the ER that mediates the nonnuclear effects of estrogen. Further studies using truncation mutants of ER or cells cultured from complete null ERKO mice may help identify the receptor or the domains of the ER that are responsible for these effects.
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Implications for SERM Development |
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Nonetheless, the central role of the ER signaling network in cancer, cardiovascular disease, osteoporosis, and neurological disease and an increasingly detailed understanding to the underlying cell biology have made ER an attractive target for pharmacological intervention. Selective estrogen receptor modulators (SERMs) are ER ligands that can have varying agonist or antagonist activities given the cell, promoter, and coregulator context130,131 (Table149–153).
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Tamoxifen, the prototypical SERM, is a triphenylethylene that, because of its agonist activity in the liver, reduces serum total cholesterol and LDL levels.132 Unfortunately, its strong agonist activity in the endometrium leads to endometrial hyperplasia and low-grade cancers. GW5638, a derivative of tamoxifen, shows some promise in early animal studies, inasmuch as it possesses estrogenic activity in preserving bone and lowering serum cholesterol while lacking agonist activity in the uterus.133
EM-800, a nonsteroidal compound, is the active form of EM-652 and demonstrates higher affinity for ER compared with E2, tamoxifen, or any other SERM.134 In addition to possessing potent antitumor activity in the uterus and breast, EM-800 prevents bone loss and lowers serum cholesterol and triglyceride levels.135 Furthermore, in vitro studies in ECs suggest that EM-800, like E2, enhances NO release by sequential activation of MAPKs and PI3K-Akt, implicating an additional vascular protective effect.136
Raloxifene, which is also a nonsteroidal compound, is similar to tamoxifen in activity although it is less agonistic in the endometrium.137 Raloxifene is administered primarily for bone preservation. Regarding its effects on the vasculature, raloxifene reduces serum triglycerides and serum fibrinogen levels.138 Raloxifene and its analogue, LY117018, stimulate eNOS activity in ECs via PI3K and ERK-dependent pathways, respectively.139,140 They have also been shown to inhibit the release of reactive oxygen species from smooth muscle cells.141 Accordingly, raloxifene treatment induces coronary artery relaxation in an ER- and NO-dependent manner.142 It also improves endothelium-dependent vasorelaxation in hypertensive rats by enhancing the expression and activity of NO synthase.141
The differential actions of estrogen and SERMs suggest complex regulatory mechanisms for suppression and activation in a context-specific manner. These mechanisms depend on the ligand, the promoter of the target gene, and the combination and exchange of coregulators.143,144 Of clinical interest, breast cancer and pituitary lactotroph tumors demonstrate enhanced apoptosis and tumor shrinkage when they are transfected with adenovirus constructs containing dominant-negative ER mutants.145 Given evidence that dominant-negative ER and anti-estrogens recruit transcriptionally repressive proteins to their DNA-binding complex that enhance their antagonistic activity,146,147 the precise regulatory proteins that govern ER activity in other disease states represent promising therapeutic strategies.
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Summary |
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We are at the threshold of understanding the full repertoire of ER action. Although the steroid receptor signaling field has made significant strides in defining its intertwining modes of action in numerous tissue types, from the nucleus to the cytoplasm and perhaps to the plasma membrane, a full understanding of how ER functions in physiological and pathophysiological states remains to be determined. Recent data from the Heart and Estrogen/Progestin Replacement Study (HERS) II trial,148 suggesting no cardiovascular benefit from extended hormone replacement therapy, underline the importance of isolating the nonnuclear mechanisms of estrogen action and delving deeper into the modulation of ER transcriptional activity by coregulators. Only after we develop a detailed understanding of these highly cell- and promoter-specific mechanisms can they be exploited for formulating clinically meaningful treatment strategies for the primary and secondary prevention of cardiovascular diseases in men and women.
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Acknowledgments |
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J.K. Liao is an Established Investigator of the American Heart Association. K.J. Ho is a Howard Hughes Medical Institute Medical Student Fellow. We thank Dr A. Senes for assistance in preparing the manuscript and Dr F. Limbourg, Dr M. Chin, and Dr. Y. Hiroi for critically reading the manuscript. We apologize to all authors whose work could not be cited because of space limitations.
Received July 23, 2002; accepted September 23, 2002.
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References |
|---|
- Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999; 340: 1801–1811.
[Free Full Text] - Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA. Estrogenic hormone action in the heart: regulatory network and function. Cardiovasc Res. 2002; 53: 709–719.
[Abstract/Free Full Text] - Stevenson JC. Cardiovascular effects of oestrogens. J Steroid Biochem Mol Biol. 2000; 74: 387–393.[CrossRef][Medline] [Order article via Infotrieve]
- White RE, Darkow DJ, Lang JL. Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism. Circ Res. 1995; 77: 936–942.
[Abstract/Free Full Text] - Bourassa PA, Milos PM, Gaynor BJ, Breslow JL, Aiello RJ. Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 1996; 93: 10022–10027.
[Abstract/Free Full Text] - Akishita M, Ouchi Y, Miyoshi H, Kozaki K, Inoue S, Ishikawa M, Eto M, Toba K, Orimo H. Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells. Atherosclerosis. 1997; 130: 1–10.[CrossRef][Medline] [Order article via Infotrieve]
- White CR, Shelton J, Chen SJ, Darley-Usmar V, Allen L, Nabors C, Sanders PW, Chen YF, Oparil S. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation. 1997; 96: 1624–1630.
[Abstract/Free Full Text] - Chen SJ, Li H, Durand J, Oparil S, Chen YF. Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery. Circulation. 1996; 93: 577–584.
[Abstract/Free Full Text] - Sullivan TR Jr, Karas RH, Aronovitz M, Faller GT, Ziar JP, Smith JJ, O’Donnell TF Jr, Mendelsohn ME. Estrogen inhibits the response-to-injury in a mouse carotid artery model. J Clin Invest. 1995; 96: 2482–2488.[Medline] [Order article via Infotrieve]
- Oparil S, Levine RL, Chen SJ, Durand J, Chen YF. Sexually dimorphic response of the balloon-injured rat carotid artery to hormone treatment. Circulation. 1997; 95: 1301–1307.
[Abstract/Free Full Text] - McHugh NA, Cook SM, Schairer JL, Bidgoli MM, Merrill GF. Ischemia- and reperfusion-induced ventricular arrhythmias in dogs: effects of estrogen. Am J Physiol. 1995; 268: H2569–H2573.[Medline] [Order article via Infotrieve]
- Node K, Kitakaze M, Kosaka H, Minamino T, Funaya H, Hori M. Amelioration of ischemia- and reperfusion-induced myocardial injury by 17ß-estradiol: role of nitric oxide and calcium-activated potassium channels. Circulation. 1997; 96: 1953–1963.
[Abstract/Free Full Text] - Farhat MY, Chen MF, Bhatti T, Iqbal A, Cathapermal S, Ramwell PW. Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in rats. Br J Pharmacol. 1993; 110: 719–723.[Medline] [Order article via Infotrieve]
- Douglas PS, Katz SE, Weinberg EO, Chen MH, Bishop SP, Lorell BH. Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload. J Am Coll Cardiol. 1998; 32: 1118–1125.
[Abstract/Free Full Text] - Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, et al. The nuclear receptor superfamily: the second decade. Cell. 1995; 83: 835–839.[CrossRef][Medline] [Order article via Infotrieve]
- Beato M, Herrlich P, Schutz G. Steroid hormone receptors: many actors in search of a plot. Cell. 1995; 83: 851–857.[CrossRef][Medline] [Order article via Infotrieve]
- Hall JM, Couse JF, Korach KS. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem. 2001; 276: 36869–36872.
[Free Full Text] - Rosenfeld MG, Glass CK. Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem. 2001; 276: 36865–36868.
[Free Full Text] - McDonnell DP, Norris JD. Connections and regulation of the human estrogen receptor. Science. 2002; 296: 1642–1644.
[Abstract/Free Full Text] - Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999; 20: 358–417.
[Abstract/Free Full Text] - Sudhir K, Chou TM, Chatterjee K, Smith EP, Williams TC, Kane JP, Malloy MJ, Korach KS, Rubanyi GM. Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation. 1997; 96: 3774–3777.
[Abstract/Free Full Text] - Sudhir K, Chou TM, Messina LM, Hutchison SJ, Korach KS, Chatterjee K, Rubanyi GM. Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene. Lancet. 1997; 349: 1146–1147.[CrossRef][Medline] [Order article via Infotrieve]
- Iafrati MD, Karas RH, Aronovitz M, Kim S, Sullivan TR Jr, Lubahn DB, O’Donnell TF Jr, Korach KS, Mendelsohn ME. Estrogen inhibits the vascular injury response in estrogen receptor -deficient mice. Nat Med. 1997; 3: 545–548.[CrossRef][Medline]
[Order article via Infotrieve]
- Karas RH, Schulten H, Pare G, Aronovitz MJ, Ohlsson C, Gustafsson JA, Mendelsohn ME. Effects of estrogen on the vascular injury response in estrogen receptor , (double) knockout mice. Circ Res. 2001; 89: 534–539.
[Abstract/Free Full Text] - Pendaries C, Darblade B, Rochaix P, Krust A, Chambon P, Korach KS, Bayard F, Arnal JF. The AF-1 activation-function of ER may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. Proc Natl Acad Sci U S A. 2002; 99: 2205–2210.
[Abstract/Free Full Text] - Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors (ER) and ß (ERß) on mouse reproductive phenotypes. Development. 2000; 127: 4277–4291.[Abstract]
- Pare G, Krust A, Karas RH, Dupont S, Aronovitz M, Chambon P, Mendelsohn ME. Estrogen receptor- mediates the protective effects of estrogen against vascular injury. Circ Res. 2002; 90: 1087–1092.
[Abstract/Free Full Text] - Zhai P, Eurell TE, Cooke PS, Lubahn DB, Gross DR. Myocardial ischemia-reperfusion injury in estrogen receptor- knockout and wild-type mice. Am J Physiol. 2000; 278: H1640–H1647.
- Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM. Estrogen receptor , not ß, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A. 2001; 98: 1952–1957.
[Abstract/Free Full Text] - Pettersson K, Gustafsson JA. Role of estrogen receptor ß in estrogen action. Annu Rev Physiol. 2001; 63: 165–192.[CrossRef][Medline] [Order article via Infotrieve]
- Lindner V, Kim SK, Karas RH, Kuiper GG, Gustafsson JA, Mendelsohn ME. Increased expression of estrogen receptor-ß mRNA in male blood vessels after vascular injury. Circ Res. 1998; 83: 224–229.
[Abstract/Free Full Text] - Zhu Y, Bian Z, Lu P, Karas RH, Bao L, Cox D, Hodgin J, Shaul PW, Thoren P, Smithies O, Gustafsson JA, Mendelsohn ME. Abnormal vascular function and hypertension in mice deficient in estrogen receptor ß. Science. 2002; 295: 505–508.
[Abstract/Free Full Text] - Collins P, Webb C. Estrogen hits the surface. Nat Med. 1999; 5: 1130–1131.[CrossRef][Medline] [Order article via Infotrieve]
- Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab. 2001; 12: 152–156.[CrossRef][Medline] [Order article via Infotrieve]
- Pietras RJ, Nemere I, Szego CM. Steroid hormone receptors in target cell membranes. Endocrine. 2001; 14: 417–427.[CrossRef][Medline] [Order article via Infotrieve]
- Luconi M, Forti G, Baldi E. Genomic and nongenomic effects of estrogens: molecular mechanisms of action and clinical implications for male reproduction. J Steroid Biochem Mol Biol. 2002; 80: 369–381.[CrossRef][Medline] [Order article via Infotrieve]
- Levin ER. Cell localization, physiology, and nongenomic actions of estrogen receptors. J Appl Physiol. 2001; 91: 1860–1867.
[Abstract/Free Full Text] - Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M. Multiple actions of steroid hormones: a focus on rapid, nongenomic effects. Pharmacol Rev. 2000; 52: 513–556.
[Abstract/Free Full Text] - Falkenstein E, Norman AW, Wehling M. Mannheim classification of nongenomically initiated (rapid) steroid action(s). J Clin Endocrinol Metab. 2000; 85: 2072–2075.
[Abstract/Free Full Text] - Falkenstein E, Wehling M. Nongenomically initiated steroid actions. Eur J Clin Invest. 2000; 30 (suppl 3): 51–54.[Medline] [Order article via Infotrieve]
- Levin ER. Cellular functions of plasma membrane estrogen receptors. Steroids. 2002; 67: 471–475.[CrossRef][Medline] [Order article via Infotrieve]
- Moggs JG, Orphanides G. Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO Rep. 2001; 2: 775–781.[CrossRef][Medline] [Order article via Infotrieve]
- Pietras RJ, Szego CM. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature. 1977; 265: 69–72.[CrossRef][Medline] [Order article via Infotrieve]
- Pappas TC, Gametchu B, Watson CS. Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J. 1995; 9: 404–410.
[Abstract/Free Full Text] - Norfleet AM, Thomas ML, Gametchu B, Watson CS. Estrogen receptor- detected on the plasma membrane of aldehyde-fixed GH3/B6/F10 rat pituitary tumor cells by enzyme-linked immunocytochemistry. Endocrinology. 1999; 140: 3805–3814.
[Abstract/Free Full Text] - Norfleet AM, Clarke CH, Gametchu B, Watson CS. Antibodies to the estrogen receptor- modulate rapid prolactin release from rat pituitary tumor cells through plasma membrane estrogen receptors. FASEB J. 2000; 14: 157–165.
[Abstract/Free Full Text] - Watson CS, Norfleet AM, Pappas TC, Gametchu B. Rapid actions of estrogens in GH3/B6 pituitary tumor cells via a plasma membrane version of estrogen receptor-. Steroids. 1999; 64: 5–13.[CrossRef][Medline]
[Order article via Infotrieve]
- Watson CS, Campbell CH, Gametchu B. The dynamic and elusive membrane estrogen receptor-. Steroids. 2002; 67: 429–437.[CrossRef][Medline]
[Order article via Infotrieve]
- Ropero AB, Soria B, Nadal A. A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas. Mol Endocrinol. 2002; 16: 497–505.
[Abstract/Free Full Text] - Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ER and ERß expressed in Chinese hamster ovary cells. Mol Endocrinol. 1999; 13: 307–319.
[Abstract/Free Full Text] - Kuroki Y, Fukushima K, Kanda Y, Mizuno K, Watanabe Y. Putative membrane-bound estrogen receptors possibly stimulate mitogen-activated protein kinase in the rat hippocampus. Eur J Pharmacol. 2000; 400: 205–209.[CrossRef][Medline] [Order article via Infotrieve]
- Watters JJ, Campbell JS, Cunningham MJ, Krebs EG, Dorsa DM. Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. Endocrinology. 1997; 138: 4030–4033.
[Abstract/Free Full Text] - Razandi M, Pedram A, Levin ER. Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Mol Endocrinol. 2000; 14: 1434–1447.
[Abstract/Free Full Text] - Berthois Y, Pourreau-Schneider N, Gandilhon P, Mittre H, Tubiana N, Martin PM. Estradiol membrane binding sites on human breast cancer cell lines: use of a fluorescent estradiol conjugate to demonstrate plasma membrane binding systems. J Steroid Biochem. 1986; 25: 963–972.[CrossRef][Medline] [Order article via Infotrieve]
- Morey AK, Razandi M, Pedram A, Hu RM, Prins BA, Levin ER. Oestrogen and progesterone inhibit the stimulated production of endothelin-1. Biochem J. 1998; 330(pt 3): 1097–1105.[Medline] [Order article via Infotrieve]
- Razandi M, Pedram A, Levin ER. Estrogen signals to the preservation of endothelial cell form and function. J Biol Chem. 2000; 275: 38540–38546.
[Abstract/Free Full Text] - Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa WC. Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. J Biol Chem. 2001; 276: 30359–30365.
[Abstract/Free Full Text] - Honda K, Sawada H, Kihara T, Urushitani M, Nakamizo T, Akaike A, Shimohama S. Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons. J Neurosci Res. 2000; 60: 321–327.[CrossRef][Medline] [Order article via Infotrieve]
- Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, Adachi K, Tasaka K, Miyoshi E, Fujiwara N, Taniguchi N, Murata Y. Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem. 2001; 276: 3459–3467.
[Abstract/Free Full Text] - Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000; 407: 538–541.[CrossRef][Medline] [Order article via Infotrieve]
- Denninger JW, Marletta MA. Guanylate cyclase and the .NO/cGMP signaling pathway. Biochim Biophys Acta. 1999; 1411: 334–350.[Medline] [Order article via Infotrieve]
- Lantin-Hermoso RL, Rosenfeld CR, Yuhanna IS, German Z, Chen Z, Shaul PW. Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. Am J Physiol. 1997; 273: L119–L126.[Medline] [Order article via Infotrieve]