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Estrogen-Independent Activation of Estrogen Receptors

2011; Lippincott Williams & Wilkins; Volume: 57; Issue: 6 Linguagem: Holandês

10.1161/hypertensionaha.111.173427

1524-4563

Matthias Barton, Matthias R. Meyer, Eric R. Prossnitz,

Nuclear Receptors and Signaling

HomeHypertensionVol. 57, No. 6Estrogen-Independent Activation of Estrogen Receptors Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBEstrogen-Independent Activation of Estrogen Receptors Matthias Barton, Matthias R. Meyer and Eric R. Prossnitz Matthias BartonMatthias Barton From the Molecular Internal Medicine (M.B., M.R.M.), University of Zurich, Zurich, Switzerland; Department of Cell Biology and Physiology (M.R.M., E.R.P.), University of New Mexico Health Sciences Center, Albuquerque, NM. , Matthias R. MeyerMatthias R. Meyer From the Molecular Internal Medicine (M.B., M.R.M.), University of Zurich, Zurich, Switzerland; Department of Cell Biology and Physiology (M.R.M., E.R.P.), University of New Mexico Health Sciences Center, Albuquerque, NM. and Eric R. ProssnitzEric R. Prossnitz From the Molecular Internal Medicine (M.B., M.R.M.), University of Zurich, Zurich, Switzerland; Department of Cell Biology and Physiology (M.R.M., E.R.P.), University of New Mexico Health Sciences Center, Albuquerque, NM. Originally published2 May 2011https://doi.org/10.1161/HYPERTENSIONAHA.111.173427Hypertension. 2011;57:1056–1057Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 See related article, pp 1161–1166Sex differences showing a lower prevalence and better outcome after ischemic stroke in women have been described, differences that are abrogated by natural or surgical menopause.1,2 High levels of endogenous estrogens in premenopausal women have been associated with reduced risk for a number of diseases, such as hypertension, diabetes mellitus, obesity, vascular disease, and stroke.2 The growing number of postmenopausal women attributed to shifts in world demographics also requires special action for the prevention and treatment of these conditions.2 Clinical and preclinical studies indicate that natural estrogens, such as 17β-estradiol, exert profound protective effects in the adult and the aging brain.1,3 Three proteins have been identified to mediate the effects of estrogens: estrogen receptor (ER) α, ERβ, and G protein–coupled ER (GPER).2,4 Although expression and function of ERα and ERβ have been well studied under physiological conditions, information about their function and expression under disease conditions, particularly in stroke,1 is still scarce.2,4Interactions Between Estrogen and the Renin-Angiotensin SystemAngiotensin is an important regulator of kidney function, inflammation, vascular tone, and, thus, cerebral perfusion.5,6 Estrogen inhibits the activity or expression of different components of the renin-angiotensin system such as angiotensin-converting enzyme (ACE), angiotensin II, or angiotensin II type 1 (AT1) receptors.6,7 Conversely, cessation of estrogen production after menopause activates the renin-angiotensin system.6 Previous studies indirectly suggested that the AT1 receptor, the predominant cellular target of angiotensin II, interacts with the function of estrogen receptors. Using a model of surgical menopause, Chappell et al8 found that the AT1 antagonist olmesartan is as effective as 17β-estradiol to suppress hypertension attributed to estrogen deficiency. Also, Tsuda et al7 reported that, in mice with atherosclerosis, neither low-dose 17β-estradiol nor olmesartan had an effect on its own on atherosclerotic lesion formation; however, in combination, lesion formation was almost completely suppressed. In addition, the AT1 antagonist losartan exerts central effects on thirst and sodium appetite in rats, which are inhibited by estrogen.9 Collectively, these findings indirectly suggested that both the renin-angiotensin system and estrogen-estrogen receptor signaling might share and/or amplify common modes of action that might be relevant for pathologies such as postmenopausal hypertension or its consequences, including myocardial infarction and stroke.Estrogen-Independent Effects on Estrogen Receptor SignalingIn the present issue of Hypertension, Shimada et al10 have now taken this issue a step further. They assessed directly, using a model of surgical menopause, the potential involvement of estrogen receptors in the protective effects of the AT1 antagonist olmesartan on cerebral infarct size and the cellular changes associated with it. In addition, this comprehensive study reports several novel findings on the role of the brain renin-angiotensin system and regulation of estrogen receptors after ischemic stroke. The investigators found that, in the brain, ACE2 is expressed at higher levels than ACE1 and that all 3 of the estrogen receptors, ERα, ERβ, and GPER, are detectable. Ovariectomy had very distinct effects on stroke-induced changes: it increased infarct size and cerebral angiotensin II and AT1 receptor expression but reduced expression of ERα, ACE2, and the AT2 receptor. On the other hand, the expression levels of ACE1, ERβ, or GPER remained unaffected by menopause or stroke. These findings are important because they demonstrate that neither components of the RAS nor estrogen receptors are regulated uniformly under the same conditions (ie, physiological processes such as menopause or diseases such as ischemic stroke). The most important findings of the study by Shimada et al10 were that olmesartan treatment not only reduced infarct size but that these effects of olmesartan were estrogen receptor dependent, that is, olmesartan increased ERα in the peri-infarct zone, an effect that was blocked by the ER antagonist ICI 182 780 (Figure). Expression of ERβ and GPER remained unaffected by stroke or olmesartan treatment. Having discovered this new and important effect of a nonestrogenic drug on ERα signaling, the investigators went on to study whether olmesartan regulates ERα function and found that olmesartan stimulates both expression and phosphorylation of ERα, but only its phosphorylation was sensitive to ERα blockade by ICI 182 780. Given the previous observations of interactions between the RAS and estrogen,7–9 these important data are the first to demonstrate a direct interaction between an AT1 antagonist and ERα, compatible with the concept that ERα-dependent activation, molecular regulation, and organ protection may occur even in the absence of estrogen.Download figureDownload PowerPointFigure. Estrogen receptor (ER)–dependent protective effects of olmesartan in ischemia-induced brain injury in estrogen (E2)-deficient states, such as menopause (natural or after ovariectomy). The angiotensin type II (AT1) receptor antagonist olmesartan (Olm) increases expression and phosphorylation of ERα. This results in upregulation of the angiotensin-converting enzyme (ACE) 2, Bcl-2, and Bcl-xL genes in an E2-independent manner, an effect that is blocked by the ERα antagonist ICI 182 780 (ICI). ICI also acts as an agonist of G protein–coupled ER (GPER). + indicates activation; −, inhibition.Implications and PerspectivesThe findings presented by Shimada et al10 leave us with several questions. First, and perhaps most important, does activation of ERα by an AT1 antagonist represent a class effect or is it simply because of the structural properties of this particular drug? Functional similarities with estrogen have been reported previously for other vasoprotective drugs, such as the β1 receptor-antagonist nebivolol.11 Second, olmesartan attenuates atherosclerosis progression,12 a disease sensitive to ERα-activation13; thus, the question remains as to how much of these olmesartan effects are mediated through ERα. In addition, novel estrogen receptors such as GPER may also affect olmesartan's cellular target.14 Indeed, olmesartan was shown recently to reduce intimal angiogenesis,12 an effect that could be explained through antiangiogenic action of GPER activation.15 Finally, and most important, is the question of whether ERα-dependent effects of olmesartan are present and required for olmesartan's effects in patients. Although olmesartan potentiates the antihypertensive effect of 17β-estradiol in postmenopausal women,16 most recently the Randomized Olmesartan and Diabetes Microalbuminuria Prevention Trial reported excess cardiovascular events and cardiovascular deaths in diabetics with cardiovascular disease.17 It can only be speculated whether the increased risk involved ERα-dependent effects of olmesartan. Also, whether the increased risk attributed to olmesartan17 is equally present in men and women is not known, because no sex-dependent subanalysis of this study is available. In any case, the work presented by Shimada et al10 provides surprising and important new pieces to the puzzle of how estrogen receptors and the renin angiotensin system interact. Whether olmesartan (or other angiotensin receptor blockers) also causes ERα activation in humans or in diseases distinct from ischemic stroke should be addressed in future studies.Sources of FundingThis work was supported by Swiss National Science Foundation grants 108258 and 122504 (to M.B.) and PBZHP3-135874 (to M.R.M.), and National Institutes of Health grants CA116662, CA18743, and CA12773 (to E.R.P.).DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Matthias Barton, Molecular Internal Medicine, University of Zurich, LTK Y44 G22, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail [email protected]uzh.chReferences1. Wise PM, Dubal DB, Rau SW, Brown CM, Suzuki S. Are estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the Women's Health Initiative. Endocr Rev. 2005; 26: 308– 312. CrossrefMedlineGoogle Scholar2. Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension. 2009; 54: 11– 18. LinkGoogle Scholar3. Dhandapani KM, Brann DW. Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol Reprod. 2002; 67: 1379– 1385. CrossrefMedlineGoogle Scholar4. Meyer MR, Haas E, Barton M. Gender differences of cardiovascular disease: new perspectives for estrogen receptor signaling. Hypertension. 2006; 47: 1019– 1026. LinkGoogle Scholar5. Miller JA, Cherney DZ, Duncan JA, Lai V, Burns KD, Kennedy CR, Zimpelmann J, Gao W, Cattran DC, Scholey JW. Gender differences in the renal response to renin-angiotensin system blockade. J Am Soc Nephrol. 2006; 17: 2554– 2560. CrossrefMedlineGoogle Scholar6. Shenoy V, Grobe JL, Qi Y, Ferreira AJ, Fraga-Silva RA, Collamat G, Bruce E, Katovich MJ. 17β-Estradiol modulates local cardiac renin-angiotensin system to prevent cardiac remodeling in the DOCA-salt model of hypertension in rats. Peptides. 2009; 30: 2309– 2315. CrossrefMedlineGoogle Scholar7. Tsuda M, Iwai M, Li JM, Li HS, Min LJ, Ide A, Okumura M, Suzuki J, Mogi M, Suzuki H, Horiuchi M. Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. Hypertension. 2005; 45: 545– 551. LinkGoogle Scholar8. Chappell MC, Gallagher PE, Averill DB, Ferrario CM, Brosnihan KB. Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen2. Lewis rat. Hypertension. 2003; 42: 781– 786. LinkGoogle Scholar9. Mecawi AS, Lepletier A, Araujo IG, Fonseca FV, Reis LC. Oestrogenic influence on brain AT1 receptor signalling on the thirst and sodium appetite in osmotically stimulated and sodium-depleted female rats. Exp Physiol. 2008; 93: 1002– 1010. CrossrefMedlineGoogle Scholar10. Shimada K, Kitazato KT, Kinouchi T, Yagi K, Tada Y, Satomi J, Kageji T, Nagahiro S. Activation of estrogen receptor-α and of angiotensin-converting enzyme 2 suppresses ischemic brain damage in oophorectomized rats. Hypertension. 2011; 57: 1161– 1166. LinkGoogle Scholar11. Garban HJ, Buga GM, Ignarro LJ. Estrogen receptor-mediated vascular responsiveness to nebivolol: a novel endothelium-related mechanism of therapeutic vasorelaxation. J Cardiovasc Pharmacol. 2004; 43: 638– 644. CrossrefMedlineGoogle Scholar12. Cheng XW, Song H, Sasaki T, Hu L, Inoue A, Bando YK, Shi G-P, Kuzuya M, Okumura K, Murohara T. Angiotensin type 1 receptor blocker reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Hypertension. 2011; 57: 981– 989. LinkGoogle Scholar13. Hodgin JB, Krege JH, Reddick RL, Korach KS, Smithies O, Maeda N. Estrogen receptor αis a major mediator of 17β-estradiol's atheroprotective effects on lesion size in Apoe−/− mice. J Clin Invest. 2001; 107: 333– 340. CrossrefMedlineGoogle Scholar14. Lindsey SH, Bhat M, Aileru A, Chappell M. GPR30 attenuates AT1 receptor expression in rat mesenteric smooth muscle cells. FASEB J. 2011; 25: 1088. CrossrefGoogle Scholar15. Holm A, Baldetorp B, Olde B, Leeb-Lundberg LM, Nilsson BO. The GPER1 agonist G-1 attenuates endothelial cell proliferation by inhibiting DNA synthesis and accumulating cells in the S and G2 phases of the cell cycle. J Vasc Res. 2011; 48: 327– 335. CrossrefMedlineGoogle Scholar16. Mirza FS, Ong P, Collins P, Okamura K, Gerhard-Herman M, Williams GH, Seely EW. Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women. Menopause. 2008; 15: 44– 50. CrossrefMedlineGoogle Scholar17. Haller H, Ito S, Izzo JL, Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011; 364: 907– 917. CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Barton M, Meyer M and Prossnitz E (2019) Nox1 downregulators: A new class of therapeutics, Steroids, 10.1016/j.steroids.2019.108494, 152, (108494), Online publication date: 1-Dec-2019. Meyer M and Barton M (2018) GPER blockers as Nox downregulators: A new drug class to target chronic non-communicable diseases, The Journal of Steroid Biochemistry and Molecular Biology, 10.1016/j.jsbmb.2017.03.019, 176, (82-87), Online publication date: 1-Feb-2018. Barton M, Filardo E, Lolait S, Thomas P, Maggiolini M and Prossnitz E (2018) Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives, The Journal of Steroid Biochemistry and Molecular Biology, 10.1016/j.jsbmb.2017.03.021, 176, (4-15), Online publication date: 1-Feb-2018. Ferris J, Li M, Leatherland J and King W (2014) Estrogen and glucocorticoid receptor agonists and antagonists in oocytes modulate the pattern of expression of genes that encode nuclear receptor proteins in very early stage rainbow trout (Oncorhynchus mykiss) embryos, Fish Physiology and Biochemistry, 10.1007/s10695-014-0021-x, 41:1, (255-265), Online publication date: 1-Feb-2015. Barton M and Meyer M (2015) Nicolaus Copernicus and the rapid vascular responses to aldosterone, Trends in Endocrinology & Metabolism, 10.1016/j.tem.2015.05.005, 26:8, (396-398), Online publication date: 1-Aug-2015. dos Santos R, da Silva F, Ribeiro R and Stefanon I Sex hormones in the cardiovascular system, Hormone Molecular Biology and Clinical Investigation, 10.1515/hmbci-2013-0048, 18:2 June 2011Vol 57, Issue 6 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.111.173427PMID: 21536981 Originally publishedMay 2, 2011 Keywordsstrokemenopauseestrogen receptorICI 182 780AT1 receptorGPR30olmesartanPDF download Advertisement SubjectsACE/Angiotensin Receptors/Renin Angiotensin SystemCerebrovascular Disease/StrokeEpidemiologyTreatmentVascular Biology