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Functional Effects and Molecular Mechanisms of Subtype-Selective ERα and ERβ Agonists in the Cardiovascular System

  • P. A. Arias-Loza
  • V. Jazbutyte
  • K.-H. Fritzemeier
  • C. Hegele-Hartung
  • L. Neyses
  • G. Ertl
  • T. Pelzer
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/1)

Abstract

Gender differences in the development of cardiovascular disease suggested for a protective function of estrogens in heart disease. The negative or neutral outcome of clinical trials on hormone replacement therapy provides clear evidence that the role of female sex hormones in the cardiovascular system is more complex than previously thought. In particular, the function of estrogens can not be understood without detailed knowledge on the specific function of both estrogen receptor subtypes in the heart and in the vasculature. In here, we review recent studies on subtype selective ERα and ERβ agonists in different animal models of hypertension, cardiac hypertrophy and vascular inflammation. The results indicate that the activation of specific ER subtypes confers specific as well as redundant protective effects in hypertensive heart disease that might ultimately translate into novel treatment options for hypertensive heart disease.

Keywords

Cardiac Hypertrophy Mineralocorticoid Receptor Hypertensive Heart Disease Mineralocorticoid Receptor Antagonist Perivascular Fibrosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Babiker FA, De Windt LJ, van Eickels M, Thijssen V, Bronsaer RJ, Grohe C, van Bilsen M, Doevendans PA (2004) 17beta-estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphate-dependent protein kinase pathway. Circulation 109:269–276PubMedCrossRefGoogle Scholar
  2. Barrett-Connor E, Bush TL (1991) Estrogen and coronary heart disease in women [see comments]. JAMA 265:1861–1867PubMedCrossRefGoogle Scholar
  3. Brilla CG, Weber KT (1992) Reactive and reparative myocardial fibrosis in arterial hypertension in the rat. Cardiovasc Res 26:671–677PubMedCrossRefGoogle Scholar
  4. Chambliss KL, Yuhanna IS, Anderson RG, Mendelsohn ME, Shaul PW (2002) ERbeta has nongenomic action in caveolae. Mol Endocrinol 16:938–946PubMedCrossRefGoogle Scholar
  5. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW (1999) Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 103:401–406PubMedCrossRefGoogle Scholar
  6. Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OH (1995) Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 91:161–170PubMedCrossRefGoogle Scholar
  7. Emmen JM, Korach KS (2003) Estrogen receptor knockout mice: phenotypes in the female reproductive tract. Gynecol Endocrinol 17:169–176PubMedGoogle Scholar
  8. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N (2002) Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 288:49–57PubMedCrossRefGoogle Scholar
  9. Green S, Walter P, Greene G, Krust A, Goffin C, Jensen E, Scrace G, Waterfield M, Chambon P (1986) Cloning of the human oestrogen receptor cDNA. J Steroid Biochem 24:77–83PubMedCrossRefGoogle Scholar
  10. Grodstein F, Stampfer M (1995) The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 38:199–210PubMedCrossRefGoogle Scholar
  11. Grohe C, Kahlert S, Lobbert K, Stimpel M, Karas RH, Vetter H, Neyses L (1997) Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett 416:107–112PubMedCrossRefGoogle Scholar
  12. Harris HA, Katzenellenbogen JA, Katzenellenbogen BS (2002) Characterization of the biological roles of the estrogen receptors ERalpha and ERbeta, in estrogen target tissues in vivo through the use of an ERalpha-selective ligand. Endocrinology 143:4172–4177PubMedCrossRefGoogle Scholar
  13. Hegele-Hartung C, Siebel P, Peters O, Kosemund D, Muller G, Hillisch A, Walter A, Kraetzschmar J, Fritzemeier KH (2004) Impact of isotype-selective estrogen receptor agonists on ovarian function. Proc Natl Acad Sci USA 101:5129–5134PubMedCrossRefGoogle Scholar
  14. Herrington DM, Howard TD (2003) From presumed benefit to potential harm–hormone therapy and heart disease. N Engl J Med 349:519–521PubMedCrossRefGoogle Scholar
  15. Hillisch A, Peters O, Kosemund D, Muller G, Walter A, Schneider B, Reddersen G, Elger W, Fritzemeier KH (2004) Dissecting physiological roles of estrogen receptor alpha and beta with potent selective ligands from structure-based design. Mol Endocrinol 18:1599–1609PubMedCrossRefGoogle Scholar
  16. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280:605–613PubMedCrossRefGoogle Scholar
  17. Iafrati MD, Karas RH, Aronovitz M, Kim S, Sullivan TR Jr, Lubahn DB, O'Donnell TF Jr, Korach KS, Mendelsohn ME (1997) Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nat Med 3:545–548PubMedCrossRefGoogle Scholar
  18. Karas RH, Schulten H, Pare G, Aronovitz MJ, Ohlsson C, Gustafsson JA, Mendelsohn ME (2001a) Effects of estrogen on the vascular injury response in estrogen receptor alpha, beta (double) knockout mice. Circ Res 89:534–539PubMedCrossRefGoogle Scholar
  19. Karas RH, van Eickels M, Lydon JP, Roddy S, Kwoun M, Aronovitz M, Baur WE, Conneely O, O'Malley BW, Mendelsohn ME (2001b) A complex role for the progesterone receptor in the response to vascular injury. J Clin Invest 108:611–618PubMedGoogle Scholar
  20. Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O (1998) Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci USA 95:15677–15682PubMedCrossRefGoogle Scholar
  21. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930PubMedCrossRefGoogle Scholar
  22. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138:863–870PubMedCrossRefGoogle Scholar
  23. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322:1561–1566PubMedCrossRefGoogle Scholar
  24. Lindberg MK, Moverare S, Skrtic S, Gao H, Dahlman-Wright K, Gustafsson JA, Ohlsson C (2003) Estrogen receptor (ER)-beta reduces ERalpha-regulated gene transcription, supporting a “ying yang” relationship between ERalpha and ERbeta in mice. Mol Endocrinol 17:203–208PubMedCrossRefGoogle Scholar
  25. Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11162–11166PubMedCrossRefGoogle Scholar
  26. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr (2004) Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 89:1045–1050PubMedCrossRefGoogle Scholar
  27. Miyata S, Minobe W, Bristow MR, Leinwand LA (2000) Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 86:386–390PubMedCrossRefGoogle Scholar
  28. Pare G, Krust A, Karas RH, Dupont S, Aronovitz M, Chambon P, Mendelsohn ME (2002) Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 90:1087–1092PubMedCrossRefGoogle Scholar
  29. Pelzer T, de Jager T, Muck J, Stimpel M, Neyses L (2002) Oestrogen action on the myocardium in vivo: specific and permissive for angiotensin-converting enzyme inhibition. J Hypertens 20:1001–1006PubMedCrossRefGoogle Scholar
  30. Pelzer T, Jazbutyte V, Hu K, Segerer S, Nahrendorf M, Nordbeck P, Bonz AW, Muck J, Fritzemeier KH, Hegele-Hartung C, Ertl G, Neyses L (2005a) The estrogen receptor-alpha agonist 16alpha-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats. Cardiovasc Res 67:604–612PubMedCrossRefGoogle Scholar
  31. Pelzer T, Loza PA, Hu K, Bayer B, Dienesch C, Calvillo L, Couse JF, Korach KS, Neyses L, Ertl G (2005b) Increased mortality and aggravation of heart failure in estrogen receptor-beta knockout mice after myocardial infarction. Circulation 111:1492–1498PubMedCrossRefGoogle Scholar
  32. Perez NG, Hashimoto K, McCune S, Altschuld RA, Marban E (1999) Origin of contractile dysfunction in heart failure: calcium cycling versus myofilaments. Circulation 99:1077–1083PubMedCrossRefGoogle Scholar
  33. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709–717PubMedCrossRefGoogle Scholar
  34. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348:1309–1321PubMedCrossRefGoogle Scholar
  35. Reckelhoff JF, Fortepiani LA (2004) Novel mechanisms responsible for postmenopausal hypertension. Hypertension 43:918–923PubMedCrossRefGoogle Scholar
  36. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321–333PubMedCrossRefGoogle Scholar
  37. Rubanyi GM, Freay AD, Kauser K, Sukovich D, Burton G, Lubahn DB, Couse JF, Curtis SW, Korach KS (1997) Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. Gender difference and effect of estrogen receptor gene disruption. J Clin Invest 99:2429–2437PubMedCrossRefGoogle Scholar
  38. Sam F, Xie Z, Ooi H, Kerstetter DL, Colucci WS, Singh M, Singh K (2004) Mice lacking osteopontin exhibit increased left ventricular dilation and reduced fibrosis after aldosterone infusion. Am J Hypertens 17:188–193PubMedCrossRefGoogle Scholar
  39. Skavdahl M, Steenbergen C, Clark J, Myers P, Demianenko T, Mao L, Rockman HA, Korach KS, Murphy E (2004) Beta estrogen receptor mediates male-female differences in the development of pressure overload hypertrophy. Am J Physiol Heart Circ Physiol 288:H4699–H476CrossRefGoogle Scholar
  40. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH (1991) Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses' health study. N Engl J Med 325:756–762PubMedCrossRefGoogle Scholar
  41. Sun J, Baudry J, Katzenellenbogen JA, Katzenellenbogen BS (2003) Molecular basis for the subtype discrimination of the estrogen receptor-beta-selective ligand, diarylpropionitrile. Mol Endocrinol 17:247–258PubMedCrossRefGoogle Scholar
  42. Sussman MA, McCulloch A, Borg TK (2002) Dance band on the Titanic: biomechanical signaling in cardiac hypertrophy. Circ Res 91:888–898PubMedCrossRefGoogle Scholar
  43. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L (1990) Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 82:1730–1736PubMedCrossRefGoogle Scholar
  44. Tardiff JC, Hewett TE, Factor SM, Vikstrom KL, Robbins J, Leinwand LA (2000) Expression of the beta (slow)-isoform of MHC in the adult mouse heart causes dominant-negative functional effects. Am J Physiol Heart Circ Physiol 278:H412–H419PubMedGoogle Scholar
  45. Vanacker JM, Pettersson K, Gustafsson JA, Laudet V (1999) Transcriptional targets shared by estrogen receptor- related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ERbeta. EMBO J 18:4270–4279PubMedCrossRefGoogle Scholar
  46. Vasan RS, Evans JC, Benjamin EJ, Levy D, Larson MG, Sundstrom J, Murabito JM, Sam F, Colucci WS, Wilson PW (2004) Relations of serum aldosterone to cardiac structure: gender-related differences in the Framingham Heart Study. Hypertension 43:957–962PubMedCrossRefGoogle Scholar
  47. Wassmann S, Baumer AT, Strehlow K, van Eickels M, Grohe C, Ahlbory K, Rosen R, Bohm M, Nickenig G (2001) Endothelial dysfunction and oxidative stress during estrogen deficiency in spontaneously hypertensive rats. Circulation 103:435–441PubMedCrossRefGoogle Scholar
  48. Young MJ, Funder JW (2002) Mineralocorticoid receptors and pathophysiological roles for aldosterone in the cardiovascular system. J Hypertens 20:1465–1468PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • P. A. Arias-Loza
    • 1
  • V. Jazbutyte
    • 1
  • K.-H. Fritzemeier
    • 2
  • C. Hegele-Hartung
    • 2
  • L. Neyses
    • 3
  • G. Ertl
    • 1
  • T. Pelzer
    • 1
  1. 1.Medizinische Klinik IUniversity of WürzburgWürzburgGermany
  2. 2.Gynecology and AndrologySchering AG, BerlinBerlinGermany
  3. 3.Division of CardiologyManchester Royal Infirmary, University of ManchesterManchesterUK

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