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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

17beta-estradiol up-regulates endothelial nitric oxide synthase (eNOS) expression in cultured endothelial cells. To clarify the role of mRNA stabilization in upregulation of eNOS expression, endothelial cells were incubated with actinomycin D as transcriptional inhibitor. Up to 10 hours incubation with 17beta-estradiol alone did not affect significantly the stability of eNOS mRNA. As tumor necrosis factor-alpha (TNF-alpha) is associated with the progression of atherosclerosis, we examined the effect of 17beta-estradiol on eNOS mRNA destabilization with TNF-alpha. After 10 hours co-incubation with TNF-alpha, relative intensity of eNOS mRNA decreased to 50% of the intensity at the start time of incubation, however, it remained significantly 1.6 times in the presence of 17beta-estradiol. This inhibitory effect of 17beta-estradiol was abolished by the treatment of estrogen receptor antagonist, ICI 182,780. This is the first finding that 17beta-estradiol stabilizes eNOS mRNA destabilized by TNF-alpha through estrogen receptor mediated mechanism.
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PMID:Estrogen prevents destabilization of endothelial nitric oxide synthase mRNA induced by tumor necrosis factor alpha through estrogen receptor mediated system. 1158 5

Epidemiological observations, clinical mechanistic studies, and basic laboratory research suggest that estrogen therapy is associated with beneficial cardiovascular effects in postmenopausal women. Estrogen has a multitude of biological effects that may account for this apparent benefit (which remains to be proved in randomized clinical trials), including favorable effects on the lipid profile, increased endothelial nitric oxide bioactivity, and enhanced fibrinolysis. However, long-term estrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the estrogen receptor, is a selective estrogen receptor modulator, producing estrogen-agonist effects in some tissues (liver, bone) and estrogen-antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis or its risk factors. This review updates the current knowledge of the biological effects of selective estrogen receptor modulators of potential cardiovascular importance in postmenopausal women.
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PMID:Selective estrogen receptor modulator effects on serum lipoproteins and vascular function in postmenopausal women and in hypercholesterolemic men. 1179 50

Endothelial nitric oxide synthase (eNOS) is expressed in vascular endothelium, airway epithelium, and certain other cell types where it generates the key signaling molecule nitric oxide (NO). Diminished NO availability contributes to systemic and pulmonary hypertension, atherosclerosis, and airway dysfunction. Complex mechanisms underly the cell specificity of eNOS expression, and co- and post-translational processing leads to trafficking of the enzyme to plasma membrane caveolae. Within caveolae, eNOS is the downstream target member of a signaling complex in which it is functionally linked to both typical G protein-coupled receptors and less typical receptors such as estrogen receptor (ER) alpha and the high-density lipoprotein receptor SR-BI displaying novel actions. This compartmentalization facilitates dynamic protein-protein interactions and calcium- and phosphorylation-dependent signal transduction events that modify eNOS activity. Further understanding of these mechanisms will enable us to take preventive and therapeutic advantage of the powerful actions of NO in multiple cell types.
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PMID:Regulation of endothelial nitric oxide synthase: location, location, location. 1182 87

There is strong evidence from both human and nonhuman primate studies supporting the conclusion that estrogen deficiency increases the progression of atherosclerosis. More controversial is the conclusion that postmenopausal estrogen replacement inhibits the progression of atherosclerosis. Estrogen treatment of older women (>65 years) with pre-existing coronary artery atherosclerosis had no beneficial effects. In contrast, estrogen treatment of younger postmenopausal women or monkeys in the early stages of atherosclerosis progression has marked beneficial effects. Whether progestogens attenuate the cardiovascular benefits of estrogen replacement therapy has been controversial for more than a decade. Current evidence from studies of both monkeys and women suggest little or no attenuation of estrogen benefits for coronary artery atherosclerosis. Lack of compliance with estrogen replacement therapy, usually because of fear of breast cancer, remains a major problem. Future regimens may overcome that fear by the co-administration of a breast cancer preventive agent (i.e., selective estrogen receptor modulators, phytoestrogens) with low dose estrogen.
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PMID:Estrogen replacement therapy, atherosclerosis, and vascular function. 1186 Oct 31

Blood vessel cells express the 2 known estrogen receptors, alpha and beta (ERalpha, ERbeta), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ERalpha and ERbeta in these events is controversial. Estrogen inhibits the vascular injury response to the same extent in ovariectomized female wild-type mice and in the original single gene knockout mice for ERalpha (ERalphaKO(Chapel Hill) [ERalphaKO(CH)]) and ERbeta (ERbetaKO(Chapel Hill) [ERbetaKO(CH)]). In double gene knockout mice generated by crossing these animals (ERalpha,betaKO(CH)), estrogen no longer inhibits medial thickening after vascular injury, but still inhibits vascular smooth muscle cell proliferation and increases uterine weight. The partial retention of estrogen responsiveness in ERalpha,betaKO(CH) mice could be due either to the presence of a novel, unidentified estrogen receptor or to functional expression of an estrogen receptor-alpha splice variant in the parental ERalphaKO(CH) mice. To distinguish between these possibilities, we studied recently generated mice fully null for estrogen receptor alpha (ERalphaKO(Strasbourg) [ERalphaKO(St)]) and examined the effect of estrogen on the response to vascular injury. In the present study, we show that after vascular injury in ovariectomized ERalphaKO(St) mice, estrogen has no detectable effect on any measure of vascular injury, including medial area, proteoglycan deposition, or smooth muscle cell proliferation. These data demonstrate that estrogen receptor-alpha mediates the protective effects of estrogen on the response to vascular injury.
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PMID:Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. 1203 98

The lipid-lowering effects of hormone replacement therapy (HRT) can only partly explain the possible decrease in cardiovascular risk noted in observational studies with hormone use in postmenopausal women. Other possible mechanisms have been explored, including the role of inflammation and coagulation factors. There is mounting evidence that inflammation plays a critical role in the pathogenesis of atherosclerosis, and it has been demonstrated that higher levels of circulating proinflammatory factors are predictive of cardiovascular events. Thus, the effects of hormones and other agents on these factors are of considerable interest. In this article, the effects of various types of HRT and estrogen receptor modulators on inflammation and coagulation markers are reviewed, and their potential impact on clinical outcomes is considered.
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PMID:Effects of hormone replacement therapy and estrogen receptor modulators on markers of inflammation and coagulation. 1210 33

Cardiovascular risk factors impair endothelium-dependent vasodilation as well as other functions of the endothelium, thereby predisposing the patient to atherosclerosis and its overt clinical manifestations. Loss of endogenous estrogen also leads to reduced bioavailability of endothelium-derived nitric oxide. In premenopausal women, the impairment of endothelial function develops within 1 month of surgical ovariectomy and is reversed by the administration of exogenous 17 beta-estradiol. Exogenous estrogen administration restores endothelial function by enhancing nitric oxide synthesis through genomic and nongenomic mechanisms and by reducing oxidative stress and nitric oxide breakdown. The effect of progesterone on endothelial function is still under investigation. In animal studies, medroxyprogesterone acetate (MPA) counteracts estrogen's beneficial effects on endothelial function and on coronary plaque size. In humans, however, the addition of progesterone to estradiol does not appreciably attenuate estrogen-associated endothelium-dependent vasodilation. Secondary prevention trials with conjugated equine estrogen plus MPA have no proven benefit in reducing coronary events, progression of angiographic coronary atherosclerosis, or incidence of cerebrovascular events. This suggests that beneficial effects of estrogen on endothelial function are counterbalanced by detrimental effects, perhaps because of proinflammatory and prothrombotic actions. The selective estrogen receptor modulators are currently under investigation as agents that might retain the favorable, without possessing the unfavorable, effects of estrogen on the vascular system.
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PMID:Vasomotor and vascular effects of hormone replacement therapy. 1210 34

As early as the 1950s, animal studies showed that exogenous estrogen could inhibit coronary atherosclerosis. Since then, additional animal studies have helped to further elucidate the cardiovascular effects of hormone replacement therapy and the importance of the timing of therapy initiation. Although estrogen's cardioprotective effects in women are believed to be related, in part, to its effects on lipoprotein levels, studies in monkeys show that estrogen acutely modulates the vasomotor response of atherosclerotic coronary arteries without significantly changing lipoprotein levels, indicating a direct vascular effect. Studies in both rats and primates indicate that some of the antiatherogenic effects of estrogens may be counteracted by specific progestins. Models using a nonselective estrogen receptor (ER) antagonist (ICI 182,780) indicate that the antiatherogenic effects of 17 beta-estradiol are mediated via ERs. Recent studies with ER knockout mice indicate that ER-alpha and ER-beta mediate the protective effects of estrogen on the vasculature. Additional studies are ongoing to define the mechanisms through which specific estrogens and progestins affect cardiovascular function and to clarify the impact of the timing of initiation of therapy on the atherosclerotic process.
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PMID:Animal models of the cardiovascular effects of exogenous hormones. 1210 36

The role of postmenopausal hormone replacement therapy (HRT) in the prevention of cardiovascular disease (CVD) has evolved since estrogen was first proposed to be vasoprotective. The discovery of novel molecular signaling pathways involving the estrogen receptor in vascular cells and the elucidation of numerous biologic mechanisms have suggested that HRT may exert its potentially beneficial or adverse cardiovascular effects through multiple mechanisms. Estrogen has genomic, as well as rapid nongenomic, effects that alter vasodilation, coagulation, inflammation, and the vascular injury response, some of which may have potentially beneficial or adverse cardiovascular consequences. Current guidelines do not support the use of HRT in the secondary prevention of CVD, and recent results of primary prevention trials show evidence of increased early cardiovascular risk and no overall health benefit with combination estrogen-progestin treatment. The role of estrogen alone in the primary prevention of CVD awaits the results of ongoing trials. The key to the use of estrogen replacement therapy for the prevention of CVD may be to target therapy before atherosclerosis is evident, and to identify women with genetic susceptibility who may be at increased risk for an adverse outcome associated with therapy.
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PMID:Postmenopausal hormone replacement therapy and atherosclerosis. 1216 39

The effects of estrogen on the female reproductive system are well known. In contrast, comparatively recent research has demonstrated that estrogen also exerts specific effects on the cardiovascular system--particularly the vasculature. This review summarizes some of the current ideas of how estrogen regulates and modulates vascular function, and focuses primarily on potential mechanisms of estrogen-induced vasodilation. Although many studies indicate estrogen exerts beneficial effects on the circulatory system, the overall conclusions from clinical studies remain somewhat equivocal. In contrast, it is clear that estrogen reduces atherosclerosis by reducing low-density lipoproteins (LDL) and inflammatory processes in the vasculature, and may also act as an antioxidant; however, these effects account for only a portion of the total cardiovascular benefit of estrogen. Estrogen is also a vasodilator and hypotensive agent, and can induce vascular relaxation by stimulating release of endothelium-derived vasodilatory substances (e.g., nitric oxide [NO]) or by acting directly on the vascular smooth muscle (VSM). Recent evidence indicates that calcium and potassium channels in VSM cells play an important role in mediating estrogen-induced relaxation of many vascular beds, but elucidating the signal transduction mechanisms coupling estrogen receptor (ER alpha and/or ER beta) activation to generation of second messengers and effector mechanisms remains an area of intense study. Not surprisingly, it is becoming apparent that the molecular basis of estrogen's influence on vascular function is multifactorial. A better understanding of these signaling mechanisms should lead to the development of powerful therapeutic agents which can maximize the many beneficial effects of estrogen action, while helping minimize the harmful (and sometimes lethal) side effects.
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PMID:Estrogen and vascular function. 1237 53


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