Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estradiol is known to exert a protective effect against the development of atherosclerosis, but the mechanism by which this protection is mediated is unclear. Since animal studies strongly suggest that production of endothelium-derived relaxing factor is enhanced by estradiol, we have examined the effect of estrogens on nitric oxide (NO) synthase (NOS) activity, protein, and mRNA in cultured bovine aortic endothelial cells. In reporter cells rich in guanylate cyclase, it has been observed that long-term treatment (> or = 24 hr) with ethinylestradiol (EE2) dose-dependently increased guanylate cyclase-activating factor activity in the conditioned medium of endothelial cells. However, conversion of L-[14C]arginine to L-[14C]citrulline by endothelial cell homogenate or quantification of nitrite and nitrate released by intact cells in the conditioned medium did not reveal any change in NOS activity induced by EE2 treatment. Similarly, Western and Northern blot analyses did not reveal any change in the endothelial NOS protein and mRNA content in response to EE2. However, EE2 dose- and time-dependently decreased superoxide anion production in the conditioned medium of endothelial cells with an EC50 value (0.1 nM) close to that which increased guanylate cyclase-activating factor activity (0.5 nM). Both of these effects were completely prevented by the antiestrogens tamoxifen and RU54876. Thus, endothelium exposure to estrogens appears to induce a receptor-mediated antioxidant effect that enhances the biological activity of endothelium-derived NO. These effects could account at least in part for the vascular protective properties of these hormones.
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PMID:Ethinylestradiol does not enhance the expression of nitric oxide synthase in bovine endothelial cells but increases the release of bioactive nitric oxide by inhibiting superoxide anion production. 863 24

Arterial dysfunction and disease affect a majority of women during their life time. Ovarian hormones inhibit the development of atherosclerosis and play an integral role in the maintenance of normal arterial function. Estrogens act in the liver to improve and maintain lipid profiles and also act in the walls of arteries and in cardiac myocytes to maintain function and prevent disease. Death from cardiovascular disease is reduced in women receiving estrogen replacement therapy (ERT). Ten-year follow-up studies of women with advanced coronary artery disease (CAD) show a marked reduction in fatalities among the women receiving estrogens compared with untreated women. Sublingual estradiol-17 beta compared with placebo results in improved exercise tolerance and reduced ischemia during exercise in women with CAD. Estradiol-17 beta infused into the coronary arteries in women with CAD leads to improved arterial function. Estrogen deficiency has been reported in women with angina pectoris who have normal coronary arteries, and these women respond to estrogen treatment. HRT implies the use of ERT with the addition of a progestin. Progestins oppose the actions of estrogens. Counter-effects of lipid metabolism appear to be minimal with progestins currently in use. Oppositional effects of progestins on hemodynamic actions of estrogens may be significant, as progestins appear to induce vasoconstriction of estrogenized vessels.
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PMID:Cardiovascular disease in women: implications of hormone replacement therapy. 882 4

In order to clarify the mechanism underlying the preventive effect of estrogen on atherogenesis, we investigated the role of estrogen in the regulation of endothelin-1 (ET-1) production and c-fos mRNA expression, which may contribute to atherogenesis. Plasma ET-1 concentration in ovariectomized rats (OVX) was twice as high as that in sham-operated female rats (Sham). Estradiol replacement in OVX rats (OVX + E) decreased plasma ET-1 to the level in Sham (Sham, 0.68 +/- 0.14; OVX, 1.32 +/- 0.14; OVX + E, 0.85 +/- 0.12 pg/ml). Metabolic clearance rate of ET-1 was similar in these three groups of rats, suggesting that the difference in plasma ET-1 was due to production rather than degradation. Measurement of immunoreactive ET-1 in tissue extract and immunohistochemical examination showed that expression of ET-1 in the aortic smooth muscle cells of OVX was increased. The expression of c-fos mRNA in the aorta was also increased in OVX compared with Sham and OVX + E. Intravenous infusion of ET-1 to Sham induced c-fos expression in the aorta, suggesting the contribution of ET-1 to c-fos expression. Tissue culture study revealed that DNA synthesis was increased in the aorta and femoral artery of OVX. These results suggest that inhibition of ET-1 and c-fos expression is involved in the anti-atherogenic action of estrogen.
Atherosclerosis 1996 Aug 23
PMID:Estrogen inhibits endothelin-1 production and c-fos gene expression in rat aorta. 883 24

25 ovariectomized women mean age 47 +/- 5 years were treated with transdermal 17 beta Estradiol in the shape of Estraderm TTS 100 plasters. Drugs were administrated in 28 days cycles during 24 weeks. Chlormadinon in daily dose 2 mg was added from 16 to 28th day of the fourth therapeutic cycle. Total cholesterol, triglycerides, HDL and LDL fractions were checked using enzymatic method. First measurement was done before the treatment, the next in the last day of every cycle. Results were statistically analysed. After treatment there were significant increase in the mean values of HDL, significant decrease of triglycerides. Changes in mean level of LDL and total cholesterol were not statistically significant. Our results seem to confirm the previous observations concerned with transdermal estrogen replacement therapy and its efficacy in atherosclerosis prophylaxis.
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PMID:[Cholesterol and its fractions in women after ovariectomy treated with estraderm TTS]. 884 30

The purpose of this study was to examine the effects on lipoprotein risk markers for CHD of oestradiol given alone and in combination with the androgenic progestogen, norethisterone. Eighty postmenopausal women were randomly allocated to receive oestradiol (2 mg/day) alone or with continuous norethisterone (1 mg/day). Serum lipoprotein levels, including lipoprotein(a), were monitored during 12 months on treatment in all the women, and in a sub-set of 32 patients cholesterol was measured in the two major density subfractions of LDL. Oestradiol caused a transient rise in triglycerides, a small decrease in LDL cholesterol (significant only at 3 and 6 months, P < 0.05) and a consistent significant increase in HDL cholesterol (16%, P < 0.01). There was a downward trend in lipoprotein(a) levels which did not achieve statistical significance. The combined preparation caused significant, sustained decreases in triglycerides (31%, P < 0.01), total cholesterol (15%, P < 0.001), VLDL (42%, P < 0.01), LDL (9%, P < 0.05) and HDL (11%, P < 0.001). Lipoprotein(a) was also reduced (39%, P < 0.05). In the sub-set of patients in which LDL subfractions were measured, the reduction in LDL induced by oestradiol monotherapy was significant only at the 3-month visit (6%, P < 0.05). This was due to a decrease in the 'light' (1.025 < d < 1.044 g/ml) subfraction (10%, P < 0.05) and resulted in an apparent shift in subfraction distribution towards the 'heavy' (1.044 < d < 1.060 g/ml) subfraction, although there was no absolute increase in the latter. None of these changes was statistically significant at 12 months. Oestradiol/norethisterone caused sustained decreases in both 'light' (15%, P < 0.05) and 'heavy' (29%, P < 0.05) subfractions, with no significant change in the relative amounts. The changes in 'light' and 'heavy' LDL in this group were highly correlated with changes in triglyceride levels (r = -0.57, P < 0.05 and r = 0.82, P < 0.01 respectively). Therefore, at the end of 1 year's treatment with unopposed oestradiol the only statistically significant change was an increase in HDL cholesterol. Addition of norethisterone to the preparation reversed this potentially beneficial change, but favourably influenced triglycerides, VLDL, LDL subfraction profile and lipoprotein(a), which may counteract the adverse effect on HDL.
Atherosclerosis 1996 Sep 27
PMID:Effects of postmenopausal hormone replacement therapy on lipoproteins including lipoprotein(a) and LDL subfractions. 887 36

The present study was performed to elucidate the mechanism underlying the anti-atherogenic action of estrogen. We investigated the effect of estrogen on intimal thickening of the rat femoral artery induced by cuff placement and further examined the effect of estrogen on migration and proliferation of vascular smooth muscle cells (VSMCs) in culture. Intimal thickening was significantly greater in males than in control females. Intimal thickening in females was increased to the level in males by ovariectomy. Estrogen replacement to ovariectomized rats reversed this effect. Proliferating cell nuclear antigen immunohistochemistry showed that in vivo proliferation of VSMCs contributed to the difference in intimal thickening. There was no difference in blood pressure and serum lipids, suggesting that estrogen directly acted on artery and inhibited intimal thickening. 17 beta-Estradiol (E2, 1-100 nmol/l) inhibited migration of cultured rat VSMCs, assayed using a microchemotaxis chamber, in a concentration-dependent manner. E2 (0.01-100 nmol/l), but not progesterone or testosterone, also inhibited [3H]thymidine incorporation in rat VSMCs in a concentration-dependent manner. Indomethacin, NG-monomethyl-L-arginine and methylene blue did not influence the inhibitory action of E2 on [3H]thymidine incorporation, suggesting that prostanoids and nitric oxide are not involved in the action of E2. E2 did not provoke VSMC injury, as measured by the release of incorporated [3H]2-deoxy-D-glucose. These results suggest that the inhibition of migration and proliferation of VSMCs contributes to the inhibitory effect of estrogen on intimal thickening.
Atherosclerosis 1997 Apr
PMID:Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells. 912 42

While estrogen is known to prevent the development of atherosclerosis, the mechanism is not completely understood. We investigated the effects of superoxide dismutase, acetylcholine, and other compounds on the release of nitric oxide (NO) by measuring the relaxation responses of aortic rings, with and without intact endothelium, taken from rabbits under various experimental conditions. The aorta of female rabbits released a greater amount of NO than did that of oophorectomized females and male rabbits. The greater basal release of NO in female rabbits was decreased in animals with atherosclerosis induced by a high cholesterol diet. We also investigated the effect of estrogen on endothelial, neuronal and inducible NO synthase (NOS), NOS-3, NOS-1 and NOS-2, respectively. Preincubation with a physiologic concentration of 17 beta-estradiol (10(-12) to 10(-8) M) over 8 h significantly enhanced the activity of NOS-3 in the endothelial cells of cultured human umbilical vein and bovine aortas. 17 beta-Estradiol also enhanced the release of NO from endothelial cells as measured by an NO selective meter and NO2-/N/3-, metabolites of NO. Western blot showed a similar effect of 17 beta-estradiol on NO. Estrogen increased NOS-3 via a receptor-mediated system. Low concentrations of 17 beta-estradiol (10(-10) to 10(-8) M) enhanced the activity of crude NOS-1 in the cytosolic fraction of rabbit cerebella. Partially purified NOS-1, obtained from the cytosolic fraction by DEAE column chromatography, had a similar response to estrogen. Estrogen at a low dose enhanced the fluorescence of dansyl calmodulin and augmented it in high doses. We also investigated the effect of estrogen on NOS-2. When J774 cells, a murine macrophage cell line, were incubated with interferon-r and lipopolysaccharide, NOS-2 was induced and a large amount of NO was released. Pre- or co-incubation of 17 beta-estradiol inhibited the induction of NOS-2 protein and NO release. The estrogen receptor antagonists, tamoxifen and ICI 182780, inhibited that effect of 17 beta-estradiol. 17 beta-Estradiol inhibited the induction of NOS-2 by a receptor-mediated system. These results may offer a new mechanism for the anti-atherosclerotic effect of 17 beta-estradiol.
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PMID:Effect of estrogen on isoforms of nitric oxide synthase: possible mechanism of anti-atherosclerotic effect of estrogen. 918 36

Evidence from numerous epidemiological and animal studies has shown a protective effect of estrogens on the development of atherosclerosis. Since not all of the beneficial effects of estrogen can be explained by alterations in plasma lipoprotein profiles, estrogens may have a direct effect on the arterial wall on one or more of the key steps in the pathogenesis of atherosclerosis. In the present study we tested the hypothesis that estrogens decrease macrophage foam cell formation by reducing lipoprotein uptake via the scavenger receptor pathway. Incubation of the human THP-1 macrophage cell line with 17 beta-estradiol reduced the uptake and metabolism of 125 I-labeled human acetylated LDL (acLDL) in a concentration-dependent manner (from 10(-9) to 10(-5) mol/L) by 30% to 40% at the highest concentrations used. This decrease was accompanied by a reduction in cholesterol accumulation and esterification. When chloroquine was used to block lysosomal degradation, 17 beta-estradiol retained its ability to decrease accumulation of acLDL. This finding suggested that the effect of estrogen occurs before degradation of acLDL by lysosomes. 17 beta-Estradiol had no effect on binding of 125I-acLDL at 4 degrees C. When 125I-acLDL was bound at 4 degrees C and warmed to 37 degrees C, less acLDL was internalized and degraded in cells treated with 17 beta-estradiol, due to greater dissociation of the bound acLDL from the surface of estrogen-treated cells during internalization. We conclude that as a result of the estrogen-induced increase in dissociation of acLDL, less lipoprotein cholesterol is delivered to macrophages, resulting in a reduced rate of foam cell formation. This may be one mechanism by which estrogens reduce the development of atherosclerosis.
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PMID:Effect of 17 beta-estradiol on metabolism of acetylated low-density lipoprotein by THP-1 macrophages in culture. 932 65

Estradiol retards the development of atherosclerosis. Animal models have suggested that NO may be a critical effector molecule in this cardiovascular protection. In this study, female human umbilical vein endothelial cells (HUVECs) were propagated in phenol red-free gonadal hormone-free medium and pretreated with 17 beta-estradiol (E2). Reduced NO2- and NO3- (NOx) concentration, determined by chemiluminescence, demonstrated a rapid increase in basal HUVEC NO release in response to physiological concentrations of E2. The estrogen receptor (ER) antagonist ICI 164,384 inhibited the augmented NO release, demonstrating an ER-mediated component of this response. Because endothelial NO synthase (eNOS) activity is largely regulated by cytosolic Ca2+, relative [Ca2+]i in response to E2 was determined in a fluorometric assay. E2 did not promote HUVEC Ca2+ fluxes. Furthermore, eNOS activity in E2-pretreated endothelial whole-cell lysates was not dependent on additional Ca2+. Despite involving the ER, this is a nongenomic effect E2, as demonstrated by maintained responses in transcriptionally inhibited cells and by the rapidly (10 minutes) of cGMP formation in an NO bioassay. We demonstrate, for the first time, that independent of cytosolic Ca2+ mobilization, there is augmentation of eNOS activity with a resultant increase in HUVEC basal NO release in response to short-term estradiol exposure. Implications for the cardiovascular protective role of estrogen are discussed.
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PMID:17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. 935 64

Estrogens have a beneficial effect on atherosclerosis and osteoporosis after menopause, but their exact mechanism of action is still unknown. The aim of the present study was to investigate the effects of estradiol and its metabolites catechol estrogens on arachidonic acid metabolism in vitro. Estradiol had no effect on arachidonic acid metabolism up to 33 microM in A23187-stimulated human whole blood. All catechol estrogens (2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol and 4-hydroxyestrone) had similar kinds of actions on arachidonic acid metabolism, being over ten times more potent inhibitors of leukotriene synthesis (IC50 values 0.044-0.16 microM) than thromboxane (IC50 values 0.99-2.1 microM) and prostaglandin E2 synthesis (IC50 values 0.84-5.5 microM). It is suggested that some of the protective actions of estrogens--e.g., on atherosclerosis and osteoporosis--may be related to the inhibition of leukotriene synthesis by catechol estrogens.
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PMID:Catechol estrogens as inhibitors of leukotriene synthesis. 941 36


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