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)

Reduced estrogen levels result in loss of protection from coronary heart disease in postmenopausal women. Enhanced and diminished atherosclerosis have been associated with plasma levels of cholesteryl ester transfer protein (CETP); however, little is known about the role of CETP-ovarian hormone interactions in atherogenesis. We assessed the severity of diet-induced atherosclerosis in ovariectomized (OV) CETP transgenic mice crossbred with LDL receptor knockout mice. Compared with OV CETP expressing ((+)), OV CETP non-expressing ((-)) mice had higher plasma levels of total, VLDL-, LDL-, and HDL-cholesterol, as well as higher antibodies titers against oxidized LDL. The mean aortic lesion area was 2-fold larger in OV CETP(-) than in OV CETP(+) mice (147 +/- 90 vs. 73 +/- 42 x 10(3) micro m(2), respectively). Estrogen therapy in OV mice blunted the CETP dependent differences in plasma lipoproteins, oxLDL antibodies, and atherosclerosis severity. Macrophages from OV CETP(+) mice took up less labeled cholesteryl ether (CEt) from acetyl-LDL than macrophages from OV CETP(-) mice. Estrogen replacement induced a further reduction in CEt uptake and an elevation in HDL mediated cholesterol efflux from pre-loaded OV CETP(+) as compared with OV CETP(-) macrophages. These findings support the proposed anti-atherogenic role of CETP in specific metabolic settings.
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PMID:Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice. 1251 20

A very large body of literature has yielded strong biologic and mechanistic plausibility for the consistent observational findings that estrogen is cardioprotective. Recently completed randomized, controlled trials have been interpreted as challenging the doctrine that hormone replacement is cardioprotective for postmenopausal women. However, other than the Estrogen in the Prevention of Atherosclerosis Trial, none of the currently completed (and no ongoing) randomized, controlled trials have appropriately tested the hypothesis generated from observational data that estrogen replacement is cardioprotective. This mainly results from the fact that randomized, controlled trials have not tested the same pattern and type of hormone use in the same population of women observed in the epidemiologic studies. On the other hand, recently completed randomized, controlled trials provide important but limited information concerning the clinical use of a specific regimen of hormone replacement for the prevention of cardiovascular disease in a particular population of postmenopausal women. Observations made from epidemiologic studies will have to be appropriately tested in randomized, controlled trials before any real conclusions can be drawn as to whether hormone replacement is cardioprotective.
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PMID:What is the cardioprotective role of hormone replacement therapy? 1256 44

Cardiovascular disease is the leading cause of death in women. In pooled analysis, observational studies have shown a 50% reduction in death and myocardial infarction among users of hormone replacement therapy (HRT) for the primary and secondary prevention of cardiovascular disease. The first randomized trial of HRT for secondary prevention of heart disease found no benefit to therapy (Heart and Estrogen/progestin Replacement Study ). Even after 6.8 years of follow-up, there was still no cardiovascular benefit from the use of HRT (HERS II). HRT was associated with a 50% increased risk of heart attacks within the first year as well as an increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) (relative risk 2.89) and gallbladder disease (RR 1.38). The Estrogen Replacement and Atherosclerosis trial found no evidence that HRT slowed the progression of subclinical angiographic disease either. This was despite a favorable effect on high-density lipoprotein and low-density lipoprotein. The first randomized trial of HRT for the primary prevention of heart disease found no overall benefit (Women's Health Initiative). The combination of estrogen and progestin resulted in a 29% increase in heart attacks, 41% increase in stroke, a doubling of thrombotic events (DVT and PE), as well as a 26% increase in breast cancer. The risk for thrombotic events was greatest in the first year whereas the risk of breast cancer increased progressively with duration of therapy. HRT is no longer recommended for the primary or secondary prevention of cardiovascular disease or stroke. It may still be considered for short-term relief of menopausal symptoms in women without high-risk conditions, but alternatives exist.
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PMID:Hormone Replacement Therapy for Primary and Secondary Prevention of Heart Disease. 1268 16

Estrogen replacement therapy (ERT) is reported to lower the incidence of cardiovascular disease in postmenopausal women. ERT also lowers the levels of oxidatively modified low-density lipoprotein (LDL). Because modified LDL can mediate the development of atherosclerosis by inflammatory processes, ERT may exert its LDL protective effect through enhanced antioxidant activity in vascular tissues. Plant sources of estrogenic compounds have been used as alternatives for ERT because they avoid a number of negative health effects produced by estrogen. In this study, the antioxidant properties of the soy isoflavone metabolite, equol (an estrogenic metabolite of daidzein) were studied. Equol has a greater antioxidant activity than the parent isoflavone compounds genistein and daidzein, found in high concentration in soy. Equol inhibits LDL oxidation in vitro and LDL oxidative modification by J774 monocyte/macrophages to LDL(-), an electronegative modified LDL found in human plasma. An antioxidant effect of equol was found to be mediated by inhibition of superoxide radical (O(2)(-*)) production and manifested through enhanced levels of free nitric oxide (NO) that prevents LDL modification. Thus, when NO levels were increased by donor agents, generators, or compounds that facilitate nitric oxide synthase activity, LDL(-) formation by J774 cells was strongly inhibited. Conversely, inhibition of NO production enhanced LDL(-) formation, and the combination of reduced NO and increased O(2)(-*) production yielded maximum LDL(-) formation. Pretreatment of cells with equol inhibited production of O(2)(-*) by J774 cells apparently via the inactivation of the reduced nicotinamide adenine dinucleotide phosphate oxidase complex. Decreased O(2)(-*) production resulted in increased free NO levels (but not total NO production) indicating that decreased reactions between O(2)(-*) and NO are an outcome of equol's antioxidant activity in cell culture.
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PMID:The phytoestrogen equol increases nitric oxide availability by inhibiting superoxide production: an antioxidant mechanism for cell-mediated LDL modification. 1272 15

Estrogen replacement therapy (ERT) has been found to be associated with increased cardiovascular risk in the first year after initiation of ERT. We compared the effects of oral and transdermal estradiol (E2) replacement therapy on markers of inflammation, coagulation and fibrinolysis in a randomized double-blind trial. Forty-three healthy women were randomized 6 weeks after surgically induced menopause to receive treatment with either oral or transdermal E2 over a period of 28 weeks. At baseline and after 28 weeks, levels of serum lipids and lipoproteins, and markers of coagulation, fibrinolysis and inflammation were determined. Among fibrinolytic parameters, oral E2 shortened euglobulin clot lysis time (P<0.05) and reduced tissue type plasminogen activator antigen (P=0.01) and plasminogen activator inhibitor activity (P<0.05). Among coagulation parameters, both routes of E2 replacement decreased fibrinogen levels (P=0.002 for oral and P=0.007 for transdermal E2). Oral E2 resulted in an increase in C-reactive protein (CRP) from 2.15 (0.71-4.05) to 3.41 (1.12-5.92) mg/l (P=0.04), while transdermal E2 showed no effect. Levels of serum amyloid A (SAA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) did not change significantly after oral and transdermal E2. Oral E2 significantly improved the lipid profile, while transdermal E2 had a less pronounced effect. Both oral and transdermal E2 significantly reduced fasting glucose. Oral E2 was associated with a pro-inflammatory response, but at the same time improved fibrinolytic capacity, showed no pro-coagulatory effects, and acted beneficially on lipids and lipoproteins. There was no influence of transdermal E2 on markers of coagulation activation, fibrinolysis and inflammation, but it decreased fibrinogen levels significantly. Further studies are needed to explore the clinical relevance of these observations.
Atherosclerosis 2003 May
PMID:Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis. 1273 95

Cardiovascular disease (CVD) is increasingly being recognised as having a profound effect on women, especially after menopause. Lack of oestrogen has been targeted as one of the reasons for increased incidence of CVD in postmenopausal women. Oestrogen has been found to have favourable effects on lipid profile, tone of vascular smooth muscle cells and fibrinogen levels. Several observational studies have supported these experimental findings, consistently demonstrating reduced cardiovascular risks in users of hormone replacement therapy (HRT). However, evidence from recent clinical trials has challenged this widespread belief. Heart and Estrogen/Progesterone Replacement Study II, Estrogen Replacement and Atherosclerosis trial and more recently, Women's Health Initiative, have shown that HRT has no role in primary and secondary prevention of CVD and most authorities currently do not advocate HRT for the prevention of CVD.
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PMID:Effect of hormone replacement therapy on cardiovascular disease: current opinion. 1273 92

Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17beta-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17beta-estradiol diminished angiotensin II-induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17beta-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17beta-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.
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PMID:Modulation of antioxidant enzyme expression and function by estrogen. 1281 84

Menopause marks the start of a new phase in a woman's life that is associated with a decrease in circulating estrogen levels. Although the average age of women has increased from 50 to nearly 85 years, the average age at menopause has remained essentially constant at 50 years. Thus, women now spend nearly a third of their lives in an estrogen deficient state. This normal aging process in women is associated with increasing health problems such as osteoporosis, cardiovascular disease, neurodegenerative diseases, and cancer. Estrogen replacement therapy (ERT) has been shown to play an important beneficial role in the health and well being of postmenopausal women. Several estrogen preparations are available and among these conjugated equine estrogens (CEE) are most frequently used. The drug CEE, is a complex natural urinary extract of pregnant mare's urine and contains at least 10 estrogens in their sulfate ester form and these are the ring B saturated estrogens: estrone (E(1)), 17beta-estradiol (17beta-E(2)), 17alpha-estradiol (17alpha-E(2)), and the ring B unsaturated estrogens equilin (Eq), 17beta-dihydroequilin (17beta-Eq), 17alpha-dihydroequilin (17alpha-Eq), equilenin (Eqn), 17beta-dihydroequilenin (17beta-Eqn), 17alpha-dihydroequilenin (17alpha-Eqn), and Delta(8)-estrone (Delta(8)-E(1)). All of these estrogens in their unconjugated form are biologically active and can interact with recombinant human estrogen receptor alpha (ERalpha) and beta (ERbeta) with 17beta-estradiol and 17beta-dihydroequilin having the highest affinity for both receptors. A number of the ring B unsaturated estrogens had nearly twofold higher affinity for the ERbeta. The pharmacokinetics of these estrogens in postmenopausal women indicate that the unconjugated estrogens compared to their sulfated forms are cleared more rapidly. The 17-keto estrogens are metabolized to the more potent 17beta-reduced products which are cleared at a slower rate. In postmenopausal women, the extent of 17beta-activation is much higher with the ring B unsaturated estrogens than with ring B saturated estrogens. Oxidized LDL and oxidative stress are thought to contribute to both atherosclerosis and neurodegenerative disorders. Neurons in particular are at a high risk from damage resulting from oxidative stress. In vivo and in vitro studies indicate that the oxidation of LDL isolated from postmenopausal women was inhibited differently by various estrogens and other antioxidants. The unique ring B unsaturated estrogens were the most potent while the red wine component t-resveratrol was the least potent. Studies were designed to explore the cellular and molecular mechanisms that may be involved in the neuroprotective effects of CEE components. The data indicate that the neurotoxic effects of oxidized LDL and glutamate can be inhibited by various estrogens, with the ring B unsaturated estrogens being the most active. These effects are involved in the inhibition of DNA fragmentation and up-regulation of anti-apoptotic protein Bcl-2 and down-regulation of pro-apoptotic protein Bax. These combined data suggest that some of the neuroprotective benefits associated with long-term estrogen therapy may occur by the above mechanism(s). Because estrogens such as the Delta(8)-estrogens are relatively less feminizing than the classical estrogen 17beta-estradiol, they may be important in the development of more neuro-specific estrogens that will be useful in the prevention of neurodegenerative diseases, such as Alzheimer's and Parkinson disease, in both men and women.
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PMID:Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's. 1294 38

A functional myeloperoxidase (MPO) promoter polymorphism, -463GA, has been associated with incidence or severity of inflammatory diseases, including atherosclerosis and Alzheimer's disease, and some cancers. The polymorphism is within an Alu element encoding four hexamer repeats recognized by nuclear receptors (AluRRE). Here we show that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists strongly regulate MPO gene expression through the AluRRE. Opposite effects were observed in granulocyte/macrophage colony-stimulating factor (GMCSF)- versus macrophage colony-stimulating factor (MCSF)-derived macrophages (Mphi): Expression was markedly up-regulated (mean 26-fold) in MCSF-Mphi and down-regulated (34-fold) in GMCSF-Mphi. This was observed with rosiglitazone and three other PPARgamma ligands of the thiazolidinedione class, as well as the natural prostaglandin metabolite 15-deoxy-Delta(12,14) prostaglandin J(2). The selective PPARgamma antagonist, GW9662, blocked both the positive and negative effects on MPO expression. Gel retardation assays showed PPARgamma bound hexamers 3/4, and estrogen receptor-alpha bound hexamers 1/2, with -463A in hexamer 1 enhancing binding. Estrogen blocked PPARgamma effects on MPO expression, especially for the A allele. Charcoal filtration of fetal calf serum eliminated the block of PPARgamma, whereas replenishing the medium with 17beta-estradiol reinstated the block. These findings suggest a model in which estrogen receptor binds the AluRRE, preventing PPARgamma binding to the adjacent site. The positive and negative regulation by PPARgamma ligands, and the block by estrogen, was also observed in transgenic mice expressing the G and A alleles. The mouse MPO gene, which lacks the primate-specific AluRRE, was unresponsive to PPARgamma ligands, suggesting the human MPO transgenes will enhance the utility of mouse models for diseases involving MPO, such as atherosclerosis and Alzheimer's.
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PMID:Peroxisome proliferator-activated receptor gamma ligands regulate myeloperoxidase expression in macrophages by an estrogen-dependent mechanism involving the -463GA promoter polymorphism. 1466 25

Estrogen therapy causes changes in a variety of cardiovascular risk factors, including insulin resistance, lipoprotein profile, haemostasis, coronary atherosclerosis and vascular reactive, that suggest a potential cardioprotective effect in postmenopausal women. With respect to the role of adjunctive progestins, currently available data suggest that the cardiovascular effects may differ depending on the type, dosage and route of administration of the progestin. Androgenic progestins antagonise the favourable cardiovascular effect of estrogens, whilst non-androgenic progestins do not impair, or may even enhance, the beneficial effect of estrogens. Therefore, less androgenic progestins would appear to be the agent of choice for combined hormone therapy in postmenopausal women with cardiovascular risk factors.
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PMID:Metabolic and vascular effect of progestins in post-menopausal women. Implications for cardioprotection. 1467 Jun 42


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