Modulation of Cardiac Hypertrophy by Estrogens
Part of the
Advances in Experimental Medicine and Biology
book series (AEMB, volume 432)
Gender-specific differences in heart disease have long been known but it has only been since the advent of molecular biology that it has become possible to investigate the molecular mechanisms.
Most biochemical work in the last 50 years has focused on the characterization of the steroid hormones involved in gender specificity. More recently, the cloning of the steroid receptors and characterization of the signaling pathways through these proteins has given new insights into the mechanisms underlying the mode of action of steroid hormones. It has also become clear that the steroid receptors can be classified into families (receptors for thyroid hormone, glucocorticoids, estrogens, androgens, retinoic acid, and so called orphan receptors of mostly unknown function). The structures of these receptors show very close resemblance and all are DNA-binding proteins acting as transcription factors. Some (if not all) act as repressors of transcription of some genes in the native state and are converted to activators (or perhaps repressors of other genes) upon binding of the cognate hormone.
Naturally, classical target tissues for estrogens and androgens have been studied first and only in very recent years has it been recognized that estrogens and androgens act on a much wider spectrum of tissues.
In the cardiovascular field, the beneficial effect of estrogen replacement therapy in postmenopausal women which reduces the incidence of cardiovascular disease by some 40% and the lower incidence of cardiovascular disease in premenopausal women have mostly been explained by the beneficial action of estrogens on the lipid profile (increase in HDL and decrease in LDL cholesterol). Recently, functional estrogen receptors have also been shown in vascular smooth muscle cells and in the endothelium.
Our own group has characterized the presence of estrogen receptors in the myocardium and in cardiac fibroblasts. We have also shown that these receptors are transcriptionally active because they are able to drive a minigene composed of a triple estrogen responsive DNA regulatory element (promoter) coupled to the firefly luciferase gene which serves as a reporter by way of its ability to drive a light-emitting reaction.
We are in the process of characterizing the target genes for estrogen in the myocardium. A specific series of immediate-early genes is induced by estradiol (the major premenopausal estrogen) and we have also characterized a number of tissue-specific genes whose expression is driven by estrogens in the myocardium.
The ultimate goal of these investigations is to explore the use of estrogens in the treatment of cardiac hypertrophy (and failure) by way of their properties to counteract (at least some of) the pathological switches in gene expression in these disease entities.
KeywordsEstrogen Receptor Cardiac Hypertrophy Cardiac Myocytes Estrogen Response Element Human Estrogen Receptor
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.
Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program follow-up study. Circulation 1987; 75:1102–1109.PubMedCrossRefGoogle Scholar
Hong MK, Romm PA, Reagan K, Green CE, Rackley CE. Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women. Am J Cardiol 1992; 69:176–178.PubMedCrossRefGoogle Scholar
Adams MR, Clarkson TB, Kaplan JR, Koritnik DR. Ovarian secretions and arteriosclerosis. In: Gutmann JN, DeCherney AH, Sarrel PM, eds. Ovarian secretions and cardiovascular and neurological function. New York: Raven Press 1990.Google Scholar
Glendy RE, Levine SA, White PD. Coronary disease in youth: comparison of 100 patients under 40 with 300 persons past 80. JAMA 1937; 109:1775–1781.CrossRefGoogle Scholar
Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991; 325:756–762.PubMedCrossRefGoogle Scholar
Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 89: 1943–1950, 1994.PubMedCrossRefGoogle Scholar
Beato M, Herrlich P, Schütz G. Steroid hormone receptors: many actors in search for a plot. Cell 1995; 83: 851–857.PubMedCrossRefGoogle Scholar
Klein-Hitpass L, Schorpp M, Wagner W, Ryffel GU. An estrogen responsive element derived from the 5’ flanking region of the xenopus vitellogenin A12 gene functions in transfected human cells. Cell 1986; 46:1053–1061.PubMedCrossRefGoogle Scholar
Walter P, Green S, Krust A, Bornert JM, Jeltsch JM, Staub A, Jensen E, Scrace G, Waterfield M, Chambon P. Cloning of the human estrogen receptor cDNA. Proc Natl Acad Sci USA 1985; 82:7889–7893.PubMedCrossRefGoogle Scholar
Kumar V, Green S, Staub A, Chambon P. Localisation of the estradiol-binding and putative DNA-binding domains of the human estrogen receptor. EMBO J 1986; 5:2231–2236.PubMedGoogle Scholar
Migliaccio A, Di Domenico M, Green S, de Falco A, Kajtaniac EL, Blasi F, Chambon P, Auricchio F. Phosphorylation on tyrosine of in vitro synthezised human estrogen receptor activates its hormone binding. Mol Endocrinol 1989; 3:1061–1069.PubMedCrossRefGoogle Scholar
Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995; 270:1491–1494.PubMedCrossRefGoogle Scholar
Jacq X, Brou C, Lutz Y, Davidson I, Chambon P, Tora L. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell 1994; 79:107–117.PubMedCrossRefGoogle Scholar
Kato S, Sasaki H, Suzawa M, Masushige S, Tora L, Chambon P, Gronemeyer H. Widely spaced, directly repeated PuGGTCA elements act as promiscuous enhancers for different classes of nuclear receptors. Mol Cell Biol 1995; 15:5858–5867.PubMedGoogle Scholar
Gaub MP, Bellard M, Scheuer I, Chambon P, Sassone-Corsi P. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell 1990; 63:1267–1276.PubMedCrossRefGoogle Scholar
Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 1993; 90:11162–11166.PubMedCrossRefGoogle Scholar
Grohe C, Kahlert S, Löbbert K, Stimpel M, Karas RH, Vetter H, Neyses L. Cardiac myocytes and fibroblasts contain functional estrogen receptors, (submitted)Google Scholar
Neyses, Nouskas J, Luycken J, Fronhoffs S, Oberdorf S, Williams RS, Sukhatme VP, Vetter H. Induction of immediate-early genes by angiotensin-2 and endothelin-1 in adult rat cardiomyocytes. J Hypertens 1993; 11:927–934.PubMedCrossRefGoogle Scholar
Dubik D, Dembinski TC, Shiu RPC. Stimulation of the c-myc oncogene expression associated with estrogeninduced proliferation of human breast cancer cells. Cancer Res 1987; 47:6517–6521.PubMedGoogle Scholar
Weisz A, Rosales R. Identification of an estrogen response element upstream of the human c-fos gene that binds the estrogen receptor and the AP-1 transcription factor. Nucleic Acids Res 1990; 18:5097–5106.PubMedCrossRefGoogle Scholar
Cicatiello L, Sica V, Bresciani F, Weisz A. Identification of a specific pattern of “immediate-early” gene activation induced by estrogen during mitogenic stimulation of rat uterine cells. Receptor 1993; 3:17–30.PubMedGoogle Scholar
Neyses L, Nouskas J, Vetter H. Inhibition of endothelin-1 induced myocardial protein synthesis by an antisense oligonucleotide against the early growth response gene-1. Biochem Biophys Res Commun 1991; 181:22–27.PubMedCrossRefGoogle Scholar
Morano I, Gagelmann M, Arner A, Ganten U, Rüegg JC. Myosin isoenzymes of vascular smooth and cardiac muscle in the spontaneously hypertensive and normotensive male and female rat: a comparative study. Circ Res 1986; 59:456–462.PubMedCrossRefGoogle Scholar
Malhotra A, Buttrick P, Scheuer J. Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats. Am J Physiol 1990; 259:H866–H871.PubMedGoogle Scholar
Morano I, Gerstner J, Rüegg JC, Ganten U. Regulation of myosin heavy chain expression in the hearts of hypertensive rats by testosterone. Circ Res 1990; 66:1585–1590.PubMedCrossRefGoogle Scholar
Neyses L, Pelzer T. The biological cascade leading to hypertrophy. Eur Heart J, 1995; 16(Suppl. N):8–11.PubMedCrossRefGoogle Scholar
Beyer EC, Paul DL, Goodenough DA. The connexin family of gap junction proteins. J Membrane Biol 1990; 116:187–194.CrossRefGoogle Scholar
Willecke K, Hennemann H, Dahl E, Jungbluth S, Heynkes R. The diversity of connexin genes encoding gap junctional proteins. Eur J Cell Biol 1991; 56:1–7.PubMedGoogle Scholar
De Leon JR, Buttrick PM, Fishman GI. Functional analysis of the connexin-43 gene promoter in vivo and in vitro. J Mol Cell Cardiol 1994; 26:379–389.PubMedCrossRefGoogle Scholar
Yu W, Dahl G, Werner R. The connexin-43 gene is responsive to estrogen. Proc R Soc Lond 1994; 255:125–132.CrossRefGoogle Scholar
Bastide B, Neyses L, Ganten D, Paul M, Willecke K, Traub O. The gap junction protein connexin-40 is preferentially expressed in vascular endothelium as well as conductive bundles of rat myocardium and is increased under hypertensive conditions. Circ Res 1993; 73:1138–1149.PubMedCrossRefGoogle Scholar
Weiner C, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci 1994; 91:5212–5216.PubMedCrossRefGoogle Scholar
Proudler AJ, Ahmed Al H, Crook D, Fogelman I, Rymer JM, Stevenson JC. Hormone replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal women. Lancet 1995; 346:89–90.PubMedCrossRefGoogle Scholar
Testut P, Soubrier F, Corvol P, Hubert C. Functional analysis of the human somatic angiotensin-I converting enzyme gene promoter. Biochem J 1993; 293:843–848.PubMedGoogle Scholar
Jiang C, Poole-Wilson PA, Sarrel PM, Mochizuki S, Collins P, McLeod KT. Effect of 17β-estradiol on concentration, Ca2+
current and intracellular free Ca2+
in guinea-pig isolated cardiac myocytes. Br J Pharmacol 1992; 106:739–745.PubMedCrossRefGoogle Scholar
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