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See detailFunctional effects and molecular mechanisms of subtype-selective ERalpha and ERbeta agonists in the cardiovascular system.
Arias-Loza, P. A.; Jazbutyte, V.; Fritzemeier, K. H. et al

in Ernst Schering Foundation symposium proceedings (2006), (1), 87-106

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 ... [more ▼]

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 ERalpha and ERbeta 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. [less ▲]

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See detailEstrogen effects in the myocardium: inhibition of NF-kappaB DNA binding by estrogen receptor-alpha and -beta.
Pelzer, T.; Neumann, M.; de Jager, T. et al

in Biochemical and biophysical research communications (2001), 286(5), 1153-7

We have previously shown that estrogen effects in the heart include direct hormone effects on the myocardium. In a recent study we found that one beneficial effect of estradiol on the myocardium is the ... [more ▼]

We have previously shown that estrogen effects in the heart include direct hormone effects on the myocardium. In a recent study we found that one beneficial effect of estradiol on the myocardium is the inhibition of apoptosis in cardiac myocytes. This effect was associated with a reduction of NF-kappaB activity. In the present study we have analyzed the functional mechanism of NF-kappaB inhibition in the myocardium by estrogen receptors-alpha and -beta. Despite the previous finding that 17-beta-estradiol (10 nM) inhibited the staurosporine-induced binding of p65/p50 NF-kappaB complexes to their cognate DNA elements in cultured rat cardiac myocytes, myocyte extracts showed no change in expression or cellular localization of p65, p50, and IkappaB upon staurosporine or estradiol treatment. Addition of either estrogen receptor-alpha or estrogen receptor-beta as recombinant protein was sufficient to inhibit staurosporine-dependent p65/p50 DNA binding in cardiac myocytes. 17-beta-Estradiol inhibits staurosporine-induced p65/p50 DNA binding associated with apoptotic cell death of cardiac myocytes via estrogen receptors-alpha and -beta. This is not associated with changes in p65, p50 and IkappaB expression or subcellular localization. Thus, inhibition of NF-kappaB activity by estrogenic compounds might inhibit NF-kappaB dependent gene expression such as pro-inflammatory cytokines in the myocardium. [less ▲]

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See detailMechanisms of estrogen receptor action in the myocardium. Rapid gene activation via the ERK1/2 pathway and serum response elements.
de Jager, T.; Pelzer, T.; Muller-Botz, S. et al

in The Journal of biological chemistry (2001), 276(30), 27873-80

We have previously shown that the myocardium is a target tissue for estrogen. Here, we have identified rapid non-nuclear estrogen effects on the expression of the early growth response gene-1 (Egr-1) in ... [more ▼]

We have previously shown that the myocardium is a target tissue for estrogen. Here, we have identified rapid non-nuclear estrogen effects on the expression of the early growth response gene-1 (Egr-1) in cardiomyocytes. Egr-1 mRNA and protein were rapidly and strongly induced by estrogen in an estrogen receptor-dependent manner via the extracellular signal-regulated kinase, ERK1/2. A promoter analysis study of a 1.2-kilobase Egr-1 promoter fragment revealed that the serum response elements (SREs) but not the estrogen response elements or AP-1 sites are responsible for Egr-1 induction by estrogen, identifying a novel mechanism of estrogen receptor-dependent gene activation in the myocardium. Both estrogen receptor-alpha and -beta induced the Egr-1 promoter via the SREs as well as an artificial promoter consisting of only five SREs in cardiomyocytes. Electrophoretic mobility shift assays showed that a protein complex containing serum response factor or an antigenically related protein was recruited to the SREs by estrogen treatment of primary cardiomyocytes. The recruitment of the protein complex was inhibited by the specific estrogen receptor antagonist ICI 182,780 as well as the MEK inhibitor PD 98059. Taken together, these results identify SREs as important promoter control elements for an estrogen receptor-dependent mechanism of gene activation in the myocardium. [less ▲]

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See detail17beta-estradiol prevents programmed cell death in cardiac myocytes.
Pelzer, T.; Neumann, M.; deJager, T. et al

in Biochemical and biophysical research communications (2000), 268(1), 192-200

The cardioprotective effects of estrogens are clearly established. However, the underlying mechanisms are poorly understood. Because programmed cell death (apoptosis) probably contributes to the loss of ... [more ▼]

The cardioprotective effects of estrogens are clearly established. However, the underlying mechanisms are poorly understood. Because programmed cell death (apoptosis) probably contributes to the loss of cardiac myocytes in heart failure and because estrogens prevent apoptosis in breast cancer cells, we investigated whether the loss of cardiac myocytes by programmed cell death could be prevented by physiological doses of 17beta-estradiol. Apoptosis of cultured cardiac myocytes was induced by staurosporine. 17beta-estradiol (10 nM) had an antiapoptotic effect as determined by morphological analysis, vital staining using the Hoechst dye 33342 and terminal transferase dUTP nick-end labeling (TUNEL). As a potential mechanism for the antiapoptotic effect of 17beta-estradiol we found a reduced activity of the ICE-like protease caspase-3 in hormone-treated myocytes. Furthermore, inhibition of apoptosis by estradiol was associated with a reduced activity of NF-kappaB transcription factors, particularly p65/RelA and p50. To our knowledge, these data provide the first indication that 17beta-estradiol in physiological concentrations inhibits apoptosis in cardiac myocytes. The antiapoptotic effect of estrogens might contribute to the known cardioprotective effect of estrogens and provides a starting point for the development of future treatment options. [less ▲]

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See detailInduction of Egr-1 mRNA and protein by endothelin 1, angiotensin II and norepinephrine in neonatal cardiac myocytes.
Shamim, A.; Pelzer, T.; Grohe, C. et al

in Molecular and cellular biochemistry (1999), 195(1-2), 11-7

The early growth response gene Egr-1 is a nuclear transcription factor known to serve as an intermediary in a broad range of signal transduction processes. Recent studies have assigned Egr-1 a new role as ... [more ▼]

The early growth response gene Egr-1 is a nuclear transcription factor known to serve as an intermediary in a broad range of signal transduction processes. Recent studies have assigned Egr-1 a new role as an amplifier of gene expression. Egr-1 mRNA is expressed in the myocardium and is rapidly induced in response to hypertrophic stimuli. However, induction of the Egr-1 protein has not yet been demonstrated in the myocardium; on the other hand, in skeletal muscle cells we have shown translational regulation of Egr-1. To further investigate the role of Egr-1 in the regulatory mechanisms of a variety of signal transduction processes we have therefore asked whether bona fide hypertrophic stimuli induce Egr-1 protein subsequently to its mRNA in neonatal rat cardiomyocytes or whether translational block occurs. In confocal laser studies the Egr-1 protein was nuclearly localized. Norepinephrine (NE, 2 microM), angiotensin II (AII, 0.1 microM), and endothelin 1 (E1, 0.1 microM) each induced the Egr-1 mRNA 6-8 fold and the Egr-1 protein 3-5 fold (n = 3, p < 0.01). Therefore, in contrast to skeletal muscle cells, these stimuli increased Egr-1 mRNA and protein levels. These results point further to the role of Egr-1 as a possible amplifier of signal transduction in the myocardium. [less ▲]

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See detailModulation of cardiac hypertrophy by estrogens.
Pelzer, T.; Shamim, A.; Wolfges, S. et al

in Zanchetti, Alberto; Devereux, Richard B.; Hansson, Lennart (Eds.) et al Hypertension and the Heart (1997)

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 ... [more ▼]

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. [less ▲]

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See detailSex specific mechanisms of cardiovascular disease
Neyses, Ludwig UL; Pelzer, T

in Stimpel, M; Zanchetti, A (Eds.) Hypertension after menopause (1997)

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See detailWas ist bei Vorhofflimmern zu beachten?
Neyses, Ludwig UL; Pelzer, T; Maas, A et al

in Der Bayerische Internist (1997), (17), 24-29

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See detailEstrogen effects in the heart.
Pelzer, T.; Shamim, A.; Neyses, Ludwig UL

in Molecular and cellular biochemistry (1996), 160-161

Gender specific differences in cardiovascular disease are largely mediated by sex hormones. The use of estrogens significantly reduces the overall incidence of heart disease in postmenopausal women ... [more ▼]

Gender specific differences in cardiovascular disease are largely mediated by sex hormones. The use of estrogens significantly reduces the overall incidence of heart disease in postmenopausal women. Beneficial effects of estrogens on plasma lipoprotein levels are clearly established. However, these do not explain the magnitude of risk reduction seen in clinical studies. Thus additional and currently unknown functions of estrogens must be operative. Elucidation of the exact estrogen action in the heart will have important implications in the treatment of cardiovascular disease. It will probably enhance the therapeutic repertoire in treating heart disease, the most common cause of death in industrialized countries. We will review the current understanding of the function of estrogens in the heart and discuss potential strategies on how to apply these data to clinical practice. [less ▲]

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See detailExpression of the plasma membrane Ca2+-ATPase in myogenic cells.
Hammes, A.; Oberdorf-Maass, S.; Jenatschke, S. et al

in The Journal of biological chemistry (1996), 271(48), 30816-22

To study the physiological function of the plasma membrane calmodulin-dependent calcium ATPase (PMCA) in intact cells, L6 myogenic cell lines stably overexpressing the human PMCA isoform 4CI (= human PMCA ... [more ▼]

To study the physiological function of the plasma membrane calmodulin-dependent calcium ATPase (PMCA) in intact cells, L6 myogenic cell lines stably overexpressing the human PMCA isoform 4CI (= human PMCA isoform 4b) were generated. Several independent L6 clones and controls stably transfected with the empty expression vector were analyzed in detail. The resting cytosolic calcium level in hPMCA4CI-overexpressing muscle cells (measured by the Fura-2 method) was significantly reduced by 20-30% compared with controls. This was shown in a cytosolic window of 1322 single cells (p < 0.01). Furthermore, the differentiation process of these cells was remarkably accelerated compared with control myoblasts and parental nontransfected L6 cells as assessed by multinucleated myotube formation and creatine phosphokinase activity elevation. After 4 and 6 days of differentiation, PMCA-overexpressing L6 cells from four independent clones displayed a 3- and 4-fold higher creatine phosphokinase activity compared with controls (n = 5, p < 0.02). These results may extend the concept of the function of the PMCA from simple prevention of calcium overload to an active involvement in intracellular calcium regulation with potentially important consequences for cellular functions. [less ▲]

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See detailThe biological cascade leading to cardiac hypertrophy.
Neyses, Ludwig UL; Pelzer, T.

in European heart journal (1995), 16 Suppl N

Cardiac hypertrophy, one of the major risk factors in hypertension, is associated with a high incidence of congestive heart failure and sudden death. Despite efforts over the last 20 years, the underlying ... [more ▼]

Cardiac hypertrophy, one of the major risk factors in hypertension, is associated with a high incidence of congestive heart failure and sudden death. Despite efforts over the last 20 years, the underlying molecular mechanisms of cardiac hypertrophy are still poorly understood, thus making it difficult to develop new therapeutic strategies. A growing body of evidence suggests that cardiac hypertrophy results from mechanical stress that triggers paracrine and autocrine signal transduction pathways. Furthermore, whereas hypertrophy leads to isoform switches in some contractile proteins, increased protein synthesis is largely based on increased translational capacity. Cardiac growth under physiological as well as pathological conditions is regulated by several recently identified transcription factors. Among the factors that are capable of transmitting hypertrophic stimuli to the nucleus is the early growth response gene-1 (Egr-1). Whereas female gender is already an established cardioprotective factor in clinical trials, some very recent data indicate that oestrogens and the nuclear oestrogen receptor may directly modulate gene expression in the development of cardiac hypertrophy. Future pharmacological interventions could be directed towards modifying the nuclear signal transduction cascade involving multiple protein kinases and phosphatases. [less ▲]

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See detail[Molecular adaptation of the heart to hypertension].
Neyses, Ludwig UL; Pelzer, T.

in Zeitschrift fur Kardiologie (1995), 84 Suppl 4

Because myocardial hypertrophy is an independent risk factor for sudden death and cardiac failure, it is important to understand its molecular mechanisms to be able to devise new treatment strategies in ... [more ▼]

Because myocardial hypertrophy is an independent risk factor for sudden death and cardiac failure, it is important to understand its molecular mechanisms to be able to devise new treatment strategies in the future. Stretch is the putative primary stimulus triggering hypertrophy. Further signal transduction steps such as auto- and paracrine secretion of growth factors or transmission via the cytoskeleton are beginning to be unravelled. Subsequent to hypertrophic stimuli some important proteins undergo an isoform switch; questitatively, however, the most important step is an increase in translational capacity for each mRNA. Myocardial specific gene expression is achieved by coordinate interaction of several transcription factors, some of which may be involved in nuclear transmission of hypertrophic signals. One of the genes capable of transmitting hypertrophic signals is the "early growth response gene-1 (Egr-1)". We have also shown that nuclear estrogen receptors act as transcription factors in the myocardium and may therefore be involved in the sex-specific modulation of cardiac hypertrophy. At present, pharmacological interventions aiming at reduction of hypertrophy by interfering with the signal transduction pathway from the membrane to the nucleus are actively being sought. These transduction pathways are composed of a series of proteinkinases which may be amenable to drugs. In the future, gene transfer may become an option for treatment. [less ▲]

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See detailIsolierte Kardiomyozyten - ein Modell zur Aufklaerung der Pathophysiologie der hypertensiven Herzkrankheit - physiologische und erste molekularbiologische Ergebnisse
Neyses, Ludwig UL; Molls, M; Pelzer, T et al

in Ganten, D (Ed.) Herz-Kreislaufregulation, Organprotektion und Organschaden (1991)

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