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

Epidemiological studies suggest that estrogens may have opposite effects on vessels: estrogens used for contraception are known to increase both arterial and venous risk, while hormone replacement therapy could reduce the risk of cardiovascular disease. In both situations, estrogens are associated with progestogens. Progestogens are rarely used alone, thus the effect of progestogens on haemostasis or vessel wall is unclear. Data can be obtained from studies using progestogens alone or from studies comparing unopposed estrogens to combined estrogen-progestogen therapy. Progestogens alone have few effect on the haemostatic system. In combined therapy used for contraception, progestogens modify the effects of estrogens on haemostasis and endothelium: the overall effect, including modifications of coagulation factors and inhibitors could a prothrombogen trend, mainly for third generation progestogens. Unopposed estrogens are also rarely used for post menopausal hormone replacement therapy (HRT). Experimental studies have shown that progestogens are able to inhibit the beneficial effect of estrogens. Two mechanisms have been suggested: first, progestogens may reduce the endothelium-dependent vasodilatator action of estrogens. Another explanation concerns the neointimal proliferation leading to atherosclerosis: Estradiol are known to reduce this proliferation. Progestogens could reduce the protective effect of estrogens. These pharmacological effect of progestogens must be taken in account to interpret the negative results of HERS study that failed to demonstrate a cardiovascular benefit of estrogens plus progestin therapy in postmenopausal women.
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PMID:[Progestogens, progesterone, coagulation and vascular tone]. 1208 38

Estradiol has numerous physiological and pathophysiological effects on the cardiovascular system, and the ongoing controversy surrounding estrogen replacement therapy clearly illustrates the importance of understanding the molecular mechanisms of estrogen action. Many recent mechanistic studies have focused on the ability of estradiol to stimulate endothelial nitric oxide synthase (eNOS) and the subsequent generation of nitric oxide (NO). NO is centrally involved in many processes such as mitogenesis, cell adhesion, thrombosis, atherosclerosis and hypertension. Consequently, elucidating the mechanisms whereby estradiol influences NO production will directly impact on our understanding of the advantages and disadvantages of estrogen replacement therapy. An exciting aspect of this emerging area of study is that the estrogen, NO and caveolae research fields have merged to identify a novel and clinically relevant molecular process. The goal of this review is to highlight the recent findings in this area and to point out areas of controversy and areas where more studies are needed.
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PMID:Caveolae, estrogen and nitric oxide. 1267 Jul 36

Estradiol prevents fatty streak formation in chow-fed atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol. In the present work, we demonstrate that the reconstitution of ApoE(-/-)/RAG-2(-/-) with bone marrow from immunocompetent ApoE(-/-)/RAG-2(+/+) mice restores the protective effect of estradiol on fatty streak constitution. We extended this demonstration to the model of low-density lipoprotein receptor-deficient mice, establishing the obligatory role of mature lymphocytes in this process. We then investigated whether the protective effect of estradiol was mediated by a specific lymphocyte subpopulation by studying the hormonal effect on fatty streak constitution in recently developed models of ApoE(-/-) mice deficient in selective T-lymphocyte subsets (either TCRalphabeta+, CD4+, CD8+, or TCRgammadelta+ lymphocytes) or B lymphocytes. In all these specifically immunodeficient mice, estradiol administration to ovariectomized mice conferred protection as in immunocompetent ApoE(-/-) mice, clearly demonstrating that no single lymphocyte subpopulation was specifically required for this effect. These results point to additional lymphocyte-dependent mechanisms such as modulating the interactions among lymphocytes and between lymphocytes and endothelial and/or antigen-presenting cells.
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PMID:The atheroprotective effect of 17beta-estradiol depends on complex interactions in adaptive immunity. 1597 70

Annexin II (ANXII) is a receptor for tissue plasminogen activator and plasminogen for the conversion to plasmin, which, in turn, induces metalloproteinase-9 (MMP-9). 17beta-Estradiol (E(2)) is reported to decrease plasminogen activity inhibitor-1 and increase plasmin and matrix metalloproteinase activity. However, the combined effects of estrogen and statins on macrophage MMP-9 activity and ANXII expression remain unclear. Treatment of J774A.1 macrophages with 1.0-100 nM of E(2) for 24h increased both MMP-9 activity and ANXII expression in a dose-dependent manner (p<0.05). Preincubation with EGTA (10mM) released ANXII from the cell membrane and inhibited the E(2)-mediated MMP-9 activity as did incubation of macrophages with anti-annexin IgG. In the presence or absence of E(2) (5 nM), simvastatin treatment in the range of 0.1-5.0 microM significantly reduced macrophage MMP-9 enzymatic activity (p<0.005) in a dose-dependent manner. In the presence or absence of E(2), simvastatin also decreased ANXII expression (p<0.05). These findings indicate that ANXII plays a central role in modulating the enzymatic activity of MMP-9 in response to E(2) and that E(2)-mediated ANXII expression and MMP-9 activity can be prevented by simvastatin. Prevention of E(2)-mediated activation of MMP-9 by simvastatin suggests that concurrent statin use may account for early event risk of myocardial infarction seen with hormone therapy in recent clinical trials.
Atherosclerosis 2006 Nov
PMID:Role of annexin II in estrogen-induced macrophage matrix metalloproteinase-9 activity: the modulating effect of statins. 1638 57

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17beta-estradiol (6 microg/d), or 2-methoxyestradiol [6.66 microg/d (low-dose) or 66.6 microg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.
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PMID:The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice. 1744 78

Osteoporosis and increased carotid intima-media thickness (IMT) have been associated with atherosclerosis. We investigated the correlation between carotid IMT and lumbar spine bone mineral density (BMD) in postmenopausal women. We studied the carotid IMT in 175 postmenopausal women, including 43 women (control) with normal spinal BMD, 73 women with osteopenia, and 59 women with osteoporosis. Carotid IMT was assessed by ultrasonography. BMD at the lumbar spine (lumbar 2 to 4 vertebrae) was measured by dual-energy X-ray absorptiometry. Age, years since menopause, and carotid IMT were significantly greater in the osteoporosis group than in the control (all p<0.01) and osteopenia groups (all p<0.01). Estradiol was significantly lower in the osteoporosis group than in the control group (p<0.05). BMD was significantly lower in the osteoporosis group than in the osteopenia or control group (both p<0.01) and in the osteopenia group than in the control group (p<0.01). After adjusting for age, years since menopause, and estradiol, women with osteoporosis had significantly greater carotid IMT than controls (p<0.05). The univariate linear regression analysis revealed that carotid IMT was significantly positively correlated with age, years since menopause, and low-density lipoprotein (LDL) cholesterol (all p<0.05) and was significantly negatively correlated with estradiol and BMD (all p<0.05), but showed no significant association with other clinical variables. In multivariate regression analysis, the carotid IMT was significantly positively correlated with LDL cholesterol (p<0.01) and negatively correlated with BMD (p<0.01), but not with other variables. Carotid atherosclerosis might be associated with lumbar spine bone mass in postmenopausal women, suggesting that postmenopausal women with osteoporosis may have more advanced carotid atherosclerosis than those with a normal bone mass.
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PMID:Relationship between carotid atherosclerosis and lumbar spine bone mineral density in postmenopausal women. 1871 68

We examined cross-sectional associations between sex hormones and carotid artery intimal-medial thickness (cIMT) and coronary artery calcium in women in the Multi-Ethnic Study of Atherosclerosis. Serum testosterone, estradiol, sex hormone binding globulin (SHBG), and dehydroepiandrosterone levels were measured in 1947 postmenopausal women aged 45-84 years (30% White, 14% Chinese-American, 31% Black, and 25% Hispanic) and not on hormone therapy. Using multiple linear regression we evaluated associations between log(sex hormone) levels and log(cIMT) adjusted for age, ethnicity, body mass index (BMI) and cardiac risk factors. Associations between sex hormone levels and the presence and extent of coronary calcium were evaluated. Total and bioavailable testosterone were positively associated with common cIMT independent of age, BMI, hypertension, smoking, HDL-cholesterol, LDL-cholesterol and insulin sensitivity (p=0.009 and p=0.002, respectively). SHBG was negatively associated with common cIMT (p=0.001) but further adjustment for BMI, cardiovascular risk factors, and LDL- and HDL-cholesterol removed significance. Estradiol and dehydroepiandrosterone were not associated with common cIMT. Sex hormones were not associated with presence of coronary calcium. Among women with measurable coronary calcium, higher SHBG (p=0.012) and lower bioavailable testosterone (p=0.007) were associated with greater coronary calcium score. No heterogeneity by ethnicity was found. In postmenopausal women, testosterone is independently associated with greater common cIMT. SHBG is negatively associated and this may be mediated by LDL- and HDL-cholesterol. In contrast, SHBG and testosterone were associated with extent of coronary calcium but in the opposite direction compared to carotid intimal-medial thickness. These differences warrant further evaluation.
Atherosclerosis 2009 May
PMID:Sex hormone levels and subclinical atherosclerosis in postmenopausal women: the Multi-Ethnic Study of Atherosclerosis. 1884 30

High-density lipoprotein (HDL) and 17beta-estradiol independently provide protection against atherosclerosis. Estradiol fatty acyl esters incorporate into HDL and whether this association enhances the atheroprotective properties of HDL is unclear. The study objective was to clarify the role that HDL-associated estradiol fatty acyl esters play in mediating the initial steps of reverse cholesterol transport. Cholesterol efflux potential from cholesterol loaded macrophage cells to HDL-associated estradiol ester or between HDL from premenopausal women and age-matched males and the cellular receptors involved were examined. Human THP-1 macrophages, loaded with [(3)H]cholesterol oleate, acetylated low-density lipoprotein, were pretreated with or without SR-BI inhibitors or an estrogen receptor antagonist and incubated with either HDL-associated estradiol oleate, HDL lacking estradiol oleate, or isolated HDL from females and males, and cholesterol efflux was measured. Cellular internalization and hydrolysis of HDL-associated [(3)H]estradiol ester were determined. HDL-associated estradiol oleate and premenopausal female HDL demonstrated significantly higher cholesterol efflux capacity to media than male HDL. SR-BI and estrogen receptor inhibition significantly reduced this effect. Cells internalized and subsequently hydrolyzed HDL-associated [(3)H]estradiol ester to [(3)H]estradiol and again SR-BI inhibition reduced this internalization. These results demonstrate that HDL-mediated macrophage cholesterol efflux potential is enhanced by HDL-associated estradiol esters.
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PMID:Human macrophage cholesterol efflux potential is enhanced by HDL-associated 17beta-estradiol fatty acyl esters. 1940 43

Clinical studies revealed unfavorable effects of hormone replacement therapy in postmenopausal women despite strong evidence for vasoprotective effects of estrogen in animal models. Therefore, an attempt was made to address adverse effects of estradiol on atherosclerosis, endothelial function, and thrombosis in a murine model of atherosclerosis. ApoE(-/-) mice were bilaterally ovariectomized (OVX) and substituted with placebo or 17-beta-Estradiol (E(2), 1.1 and 6.6 microg/day) on Western diet for 90 days. Low-dose E(2) (1.1 microg/day) treatment significantly increased atherosclerotic plaque score, whereas high-dose E(2) (6.6 microg/day) reduced aortic plaque burden. The proatherosclerotic effects of low-dose E(2) were associated with decreased total collagen in aortic root lesions and impaired acetylcholine (ACh)-induced vasorelaxation of aortic rings. On the contrary, OVX compared with control reduced atherosclerosis, increased fibrillar collagen and improved endothelial function. The thrombotic response as measured in a photothrombosis model was not significantly altered by E(2) or OVX. Taken together, differential effects on atherosclerosis of the clinical relevant low-dose E(2) compared with high-dose E(2) were demonstrated. Importantly, the presented experimental conditions provide a model to study the untoward vascular effects of E(2) in the context of accelerated and advanced atherosclerosis.
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PMID:Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice. 2017 92

The association between physiologic levels of sex hormones and QT-interval duration in humans was evaluated using data from 727 men enrolled in the Third National Health and Nutrition Examination Survey and 2,942 men and 1,885 postmenopausal women enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Testosterone, estradiol, and sex hormone-binding globulin levels were measured in serum and free testosterone was calculated from those values. QT interval was measured using a standard 12-lead electrocardiogram. In men from the Third National Health and Nutrition Survey, the multivariate adjusted differences in average QT-interval duration comparing the highest quartiles with the lowest quartiles of total testosterone and free testosterone were -8.5 ms (95% confidence interval (CI): -15.5, -1.4) and -8.0 ms (95% CI: -13.2, -2.8), respectively. The corresponding differences were -1.8 ms (95% CI: -3.8, -0.2), and -4.7 ms (95% CI: -6.7, -2.6), respectively, in men from MESA and -0.6 ms (95% CI: -3.0, 1.8) and 0.8 ms (95% CI: -1.6, 3.3), respectively, in postmenopausal women from MESA. Estradiol levels were not associated with QT-interval duration in men, but there was a marginally significant positive association in postmenopausal women. The findings suggest that testosterone levels may explain differences in QT-interval duration between men and women and could be a contributor to population variability in QT-interval duration among men.
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PMID:Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis. 2208 27


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