17β-Estradiol Inhibits Apoptosis of Endothelial Cells

Department of Medicine, The Johns Hopkins University, Baltimore, Maryland, 21287, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 09/1997; 237(2):372-81. DOI: 10.1006/bbrc.1997.7085
Source: PubMed


Endothelial cells provide an antithrombotic and anti-inflammatory barrier for the normal vessel wall. Dysfunction of endothelial cells has been shown to promote atherosclerosis, and normalization of previously dysfunctional endothelial cells can inhibit the genesis of atheroma. In normal arteries, endothelial cells are remarkably quiescent. Acceleration of the turnover rate of endothelial cells can lead to their dysfunction. Apoptosis is a physiological process that contributes to vessel homeostasis, by eliminating damaged cells from the vessel wall. However, increased endothelial cell turnover mediated through accelerated apoptosis may alter the function of the endothelium and therefore, promote atherosclerosis. Apoptotic endothelial cells can be detected on the luminal surface of atherosclerotic coronary vessels, but not in normal vessels. This finding links endothelial cell apoptosis and the process of atherosclerosis, although a causative role for apoptosis in this process remains hypothetical. Estrogen metabolites have been shown to be among the most potent anti-atherogenic agents available to date for post-menopausal women. The mechanism of estrogen's protective effect is currently incompletely characterized. Here we show that 17beta-estradiol, a key estrogen metabolite, inhibits apoptosis in cultured endothelial cells. Our data support the hypothesis that 17beta-estradiol's anti-apoptotic effect may be mediated via improved endothelial cell interaction with the substratum, increased tyrosine phosphorylation of pp125 focal adhesion kinase, and a subsequent reduction in programmed cell death of endothelial cells. Inhibition of apoptosis by estrogens may account for some of the anti-atherogenic properties of these compounds.

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Available from: Chi V Dang, Sep 28, 2015
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    • "This culture medium maintained both EC (for which it was designed) and endometrium, since the appearance of disaggregated endometrium after 4 days in this culture medium was equivalent to that of endometrium cultured in DMEM/Hams F12 (50:50 mix) supplemented with 10% FCS (data not shown). No reproductive steroids were added to the culture medium since reproductive steroids (Morales et al., 1995; Alvarez et al., 1997) and their metabolites (Yue et al., 1997) have been show to affect EC. Disaggregated monolayer cultures were chosen in preference to explant cultures to maintain optimal oxygenation and nutrition for all cells, and to allow visible assessment of endometrial cell viability. "
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    Full-text · Article · Nov 2004 · Human Reproduction
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    • "For instance, E 2 has been shown to regulate the production of fibroblast growth factor 1 in normal and cancer breast cells [10], to activate proteins involved in the cell cycle control, such as G1 cyclins [11] [12] [13] and to stimulate expression of genes required for cell division such as the proto-oncogene c-myc [14]. However, little attention has been paid to the possibility that E 2 -activated signal transduction pathways may interact with those pathways controlling apoptosis (programmed cell death), although several studies did reveal positive and negative effects of steroids on apoptosis of noncancer cells [15] [16] [17]. Here we review the E 2 -activatable cell signaling events that are susceptible to modulating programmed cell death. "
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    ABSTRACT: It is known that steroids can induce cell surface receptor aggregation followed by activation of receptor and nonreceptor tyrosine kinases. It has been shown recently that 17beta-estradiol (E2) can stimulate the Src/p21ras/mitogen-activated protein kinase pathway in breast cancer cells, and this effect is supposed to mediate the E2-induced stimulation of breast cancer cell proliferation, possibly via activation of the c-fos and c-jun early genes or of genes involved in cell cycle control. Here we demonstrate the existence of an alternative mechanism of the cancer-promoting effect of E2. Human breast cancer cells (MCF-7) were exposed to the known proapoptotic agent vitamin E succinate (VES), added alone or together with different concentrations of E2. E2 conjugated with bovine serum albumin (E2-BSA), which cannot cross the plasma membrane of living cells, was also used in some experiments to assess whether E2 acted on the cell surface or at intracellular receptors. Apoptosis was analyzed by fluorescence-activated cell sorting after cell staining with propidium iodide and FITC-labeled annexin V. E2 showed a concentration-dependent stimulatory effect on spontaneous apoptosis but inhibited the VES-induced apoptosis. However, effects produced by the same molar concentrations of E2 were different when the hormone was free and when it was used in the form of the E2-BSA conjugate. The effects of E2 and E2-BSA were sensitive to genistein, a tyrosine kinase inhibitor. These data show that E2 modulates apoptosis of breast cancer cells, probably acting both at the cell surface and inside the cells. Tyrosine phosphorylation is involved in the signaling pathways mediating this E2 effect.
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    ABSTRACT: Abstract: Atherogenesis shares many features with inflammatory and immunal reactions. Bacterial endotoxin (LPS), together with T-lymphocytes cytokine interferon-gamma (IFN), causes inflammation and immune response. Because of its strategic anatomic position, endothelial cells are a primary target for injury and cardiovascular risk factors. A simple method for isolating and culturing mouse aortic endothelial cells (MAEC) was developed for studying the endothelial injury and activation by these stimuli in vitro (Section I). The effects of LPS and IFN, in the absence and presence of hypercholesterolemia, a traditional risk factor for atherosclerosis, on endothelial function and pro-inflammatory gene expression in vivo were also studied (Section II). We found that LPS and IFN synergistically activated MAEC by upregulating pro-inflammatory genes, such as inducible nitric oxide synthase and vascular cell adhesion molecule-1. Several signal transduction pathways, such as the Janus kinase/signal transducer and activator of transducer-1 (STAT1), the p38 mitogen-activated protein kinase, and the protein kinase A pathways, were involved in this regulation. Other effects of LPS included inducing the production of superoxide anion and hydrogen peroxide by MAEC. These reactive oxygen species, especially oxidized low-density lipoprotein cholesterol, caused MAEC injury, DNA breakage and gene expression. The in vivo effects of inflammation in endothelial dysfunction and atherogenesis were studied using a mouse model (C57BL/6) on an atherogenic diet. A single low dose of LPS (1.0 mg/kg, intraperitoneal injection) caused an impairment of endothelial-dependent vasorelaxation in response to acetylcholine in these mice but not their normal diet fed littermates. Endothelial-independent vasorelaxation remained unaffected. Chronic treatment with LPS (once a week for 12 weeks) or 16-week of the atherogenic diet each caused endothelial dysfunction. A more significant effect was observed with the combination of a low dose of LPS (0.5 mg/kg) and the atherogenic diet. The impairment of endothelial function by the atherogenic diet was lesser in STAT1 knockout mice. Overall, our results presented here suggest that multiple factors, such as inflammation, oxidation, and hypercholesterolemia, are involved in endothelial cell activation and dysfunction. These mechanistic insights of endothelial biology will provide new therapy for the cardiovascular disease, especially atherosclerosis. Title from first page of PDF file. Document formatted into pages; contains xx, 475 p.; also includes graphics. Thesis (Ph. D.)--Ohio State University, 2004. Includes bibliographical references (p. 409-442). System requirements: World Wide Web browser and PDF viewer.
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