Statins have anti-inflammatory properties, so they should lower serum C-reactive protein. The effects of this in patients with coronary artery disease are discussed.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SIK, UILJ, UKNU, UL, UM, UPCLJ, UPUK, VSZLJ
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•A six-carbon d-ring increased the antioxidant activity of estrogen analogues.•Estrogen analogues with a fluorine atom at C-2 were potent antioxidants.•Unsaturated analogues with a ...substituted 3-OH group inhibited lipid peroxidation.
Many known estrogens, both natural and synthetic, may act as antioxidants. We designed and synthesized 22 novel estrogen analogues with different ring junctions or substitutions, such as fluorine. We studied the antioxidant capacity in vitro of 35 synthetic estrogen analogues in aqueous lipoprotein solution by monitoring the formation of conjugated dienes. In addition to a free C-3 hydroxyl group, the two most active antioxidants had either a methyl group at C-4 and a six-carbon D-ring, or a fluorine atom at C-2 and an unsaturated B-ring. Extension of the D-ring increased the antioxidant capacity of 6-oxa estrogens. Compounds with a fluorine atom at C-2 were similar or more potent antioxidants compared with the principal endogenous estrogen, 17β-estradiol. In compounds with a substituted C-3 hydroxyl group, the antioxidant capacity could be significantly increased by additional double bonds in the C- or D-rings. In conclusion, we show that the antioxidant capacity of estrogen analogues could be increased by structural changes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Similarities in certain biochemical variables between preeclampsia and the insulin resistance syndrome imply a possible link between insulin resistance and preeclampsia. We measured insulin ...sensitivity by the minimal model technique between 29 and 39 weeks of gestation in 22 preeclamptic and 16 control women, whose glucose tolerance was first confirmed as normal by an oral glucose tolerance test. In addition, we measured the fasting levels of serum C-peptide, uric acid, lipids, and lipoproteins. Preeclamptic women showed a higher insulin response (
P = .001) during the oral glucose tolerance test than the controls. Insulin sensitivity in preeclamptic women (1.11 ± 0.15 × 10
−4 · min
−1 · μU/mL) was 37% lower (
P = .009) than in control women (1.77 ± 0.19 × 10
−4 · min
−1 · μU/mL). The free fatty acid (FFA) concentration in preeclamptic women (0.17 ± 0.01 g/L,
P = .0004) was 70% higher than in control women (0.10 ± 0.01 g/L). Also, baseline serum levels of C-peptide, uric acid, and triglyceride were higher in preeclamptic women. Insulin sensitivity increased fourfold to fivefold within the first 3 postpartum months, but insulin sensitivity in preeclamptic women was still 26% lower (
P = .04) than in control women. Preeclampsia is a state of increased insulin resistance, and it persists for at least 3 months after pregnancy. This may be a pathogenetic factor in preeclampsia and may contribute to the excess cardiovascular morbidity among women with prior preeclampsia.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The oxidative modification of lipoprotein particles is an important step in atherogenesis. Estrogens are known to be powerful antioxidants independently of their binding to the estrogen receptors and ...the hormonal functions. We explored the structural determinants for the antioxidant activity of a large number of estrogen derivatives (
n
=
43) in an aqueous lipoprotein solution in vitro by monitoring formation of conjugated dienes. Our results indicate that estrogen derivatives with an unsubstituted A-ring phenolic hydroxyl group with one or two adjacent methoxy groups provide strongest antioxidant protection of low density lipoprotein (LDL) and high density lipoprotein (HDL). The electron donating methoxy groups may enhance the antioxidant effect by weakening the phenolic O
H bond and providing stability to the formed phenoxyl radical. With some exceptions, compounds completely lacking unsubstituted hydroxyl groups in the A-ring exhibited no antioxidant effect, e.g. the most hydrophilic “tetrol” compound with three unsubstituted A-ring hydroxyl groups had no antioxidant effect. Moreover, additional hydroxyl groups in the B-, C- or D-ring seemed to weaken the antioxidant effect. Accordingly, both the presence of unsubstituted hydroxyl groups and adjacent substituents, as well as the lipophilicity of the derivatives determine the antioxidant activity of estrogen derivatives in aqueous lipoprotein solutions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
▶ DHEA ester-enriched HDL induce arterial vasorelaxation
via SR-B1-facilitated pathway. ▶ SR-B1 contributes to the uptake of HDL-associated DHEA fatty acyl esters by HUVEC. ▶ Cultured human ...endothelial cells hydrolyze HDL-associated DHEA fatty acyl esters.
Dehydroepiandrosterone (DHEA) fatty acyl esters once incorporated in high density lipoprotein (HDL) induce a stronger vasodilatory response in rat mesenteric arteries
ex vivo compared to native HDL. We studied the role of HDL receptor, scavenger receptor class B, type 1 (SR-B1), as well as estrogen and androgen receptors in the vasodilatory response of HDL-associated DHEA fatty acyl esters. Using cultured human vascular endothelial cells (HUVEC), we investigated the possible internalization and cellular response of HDL-associated DHEA esters. We prepared DHEA ester-enriched HDL by incubating human plasma in the presence of DHEA. After isolation and purification, HDL was added in cumulative doses to arterial rings precontracted with noradrenaline. Inhibition of the function of SR-B1 almost completely abolished maximal vasorelaxation by DHEA-enriched HDL while estrogen or androgen receptor blockage had no significant effect. When HUVECs were incubated in the presence of
3HDHEA ester-enriched HDL, the amount of intracellular
3H-radioactivity increased steadily during 24
h. Blocking of SR-B1 reduced this uptake by a mean of 30%. The proportion of unesterified
3HDHEA, as analyzed by thin-layer chromatography, increased intracellularly and in the cell culture media after several hours of incubation of the cells in the presence of
3HDHEA ester-enriched HDL. This indicated slow hydrolysis of DHEA fatty acyl esters and subsequent excretion of unesterified DHEA by the cells. In conclusion, DHEA-enriched HDL induced vasorelaxation
via the SR-B1-facilitated pathway. However, this vasodilation is not likely to be attributed to rapid hydrolysis of HDL-associated DHEA esters by the vascular endothelium.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Menopausal hot flashes may affect vascular function and perhaps explain conflicting data on cardiovascular disease (CVD) between observational and randomized hormone therapy (HT) studies. We ...prospectively assessed hot flash status in recently postmenopausal women and related it to a number of biochemical vascular surrogate markers for CVD.
Healthy, nonsmoking women (n = 150) exhibiting a broad range (no, mild, moderate, severe) of hot flashes and an onset of menopause within the previous 0.5 to 3 years were studied with laboratory tests for lipids, lipoproteins, apolipoproteins, high-sensitivity C-reactive protein, and sex hormone-binding globulin.
Apart from marked differences in hot flashes, the groups showed comparable levels of estrone, estradiol, or free estradiol index. The levels of total cholesterol (3.7-9.1 mmol/L) were similar between the groups (P = 0.744), and hypercholesterolemia (>6.5 mmol/L) was encountered equally often (P = 0.699). No difference was seen in high-, low-, or very low-density lipoproteins, triglycerides, apolipoprotein A-1, apolipoprotein B (or their ratio), or lipoprotein(a) between the groups. The levels of sex hormone-binding globulin and high-sensitivity C-reactive protein correlated negatively with each other (r = -0.204; P = 0.013) but showed no dependence on hot flashes (P = 0.531 and P = 0.215, respectively).
No baseline difference in lipid or nonlipid CVD risk factors was observed between women with hot flashes (potential HT users) and women with no or mild hot flashes (potential HT nonusers). This may imply that hot flash status per se cannot explain the difference between observational and randomized trials.
Background. Few studies have looked into the ability of measurements of apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1) or apoB/apoA-1 to predict new coronary heart disease (CHD) events in ...patients with CHD on statin treatment.
Aims. In the IDEAL trial, to compare lipoprotein components to predict CHD events and to what degree differences in those parameters could explain the observed outcome.
Methods. We compared the ability of treatment with atorvastatin 80 mg/day to that of simvastatin 20-40 mg/day to prevent CHD events in patients with CHD and used Cox regression models to study the relationships between on-treatment levels of lipoprotein components to subsequent major coronary events (MCE).
Findings. Variables related to low-density lipoprotein cholesterol (LDL-C) carried more predictive information than those related to high-density lipoprotein cholesterol (HDL-C), but LDL-C was less predictive than both non-HDL-C and apoB. The ratio of apoB to apoA-1 was most strongly related to MCE. However, for estimating differences in relative risk reduction between the treatment groups, apoB and non-HDL-C were the strongest predictors.
Interpretation. The on-treatment level of apoB/apoA-1 was the strongest predictor of MCE in the pooled patient population, whereas apoB and non-HDL-C were best able to explain the difference in outcome between treatment groups. Measurements of apoB and apoA-1 should be more widely available for routine clinical assessments.
Objective: Association of maternal angiopoietin-like protein 6 (Angptl6) levels with subsequent development of pregnancy-induced hypertension (PIH). Methods: At 24 and 32 weeks of gestation in 47 ...relatively overweight (BMI 24 kg/m2), nulliparous pregnant women serum concentrations of Angptl6 were quantified prospectively. Insulin sensitivity and lipids were measured at 24 weeks. Results: Angptl6 levels at 24 weeks, but not at 32 weeks, were significantly higher in women with subsequent PIH. Metabolic factors at 24 weeks did not correlate with Angptl6 levels. Conclusion: This preliminary study suggests that in the second trimester, Angptl6 levels are higher in women with subsequent PIH.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Dehydroepiandrosterone (DHEA) and high-density lipoprotein (HDL) are both vascular relaxants. In the circulation, HDL transports DHEA fatty acyl esters (DHEA-FAEs), which are naturally occurring ...lipophilic derivatives of DHEA. We studied in isolated rat mesenteric arteries whether HDL-associated DHEA-FAE improves the vasodilatory effect of HDL.
To prepare DHEA-FAE-enriched HDL, we incubated DHEA with human plasma. After incubation, HDL was isolated, purified, and added in cumulative doses (0.1–125μg/ml) to noradrenaline-precontracted rat arterial rings. DHEA-FAE-enriched HDL caused a dose-dependent relaxation (maximal 43±4%), which was significantly stronger than the effect of HDL from the control incubation without addition of DHEA (25±2%, p<0.001). When plasma incubation of DHEA was carried out in the presence of lecithin:cholesterol acyltransferase (LCAT) inhibitor, the relaxation response to HDL (25±3%) did not differ from the control HDL (p=0.98). Pretreatment of the arterial rings with nitric oxide synthase (NOS) antagonist impaired the relaxation response to DHEA-FAE-enriched HDL (43±4% vs. 30±3%, p=0.008). Similar experiments were performed with 17β-estradiol (E2). Compared to control HDL, E2-FAE-enriched HDL induced slightly but non-significantly stronger relaxation.
DHEA-FAE-enriched HDL was a stronger vasodilator than native HDL, and vascular relaxation was in part mediated by NOS, suggesting that DHEA-FAE may improve HDL's antiatherogenic function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Multivariate analyses identified TC, HDL-C, non-HDL-C, apoB/apoA1 ratio, and TC/HDL-C ratio as significant predictors; age-adjusted analyses found LDL-C to be significant predictor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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