Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits.

Haarbo, Jens; Leth-Espensen, Per; Stender, Steen; Christiansen, Claus

doi:10.1172/jci115129

Cited by 199 publications

(90 citation statements)

References 27 publications

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“…[1][2][3][4] Estrogen therapy has been demonstrated to lower serum LDL cholesterol, lipoprotein (a), to increase HDL cholesterol, and to have cardioprotective properties that were independent of serum lipoprotein modulation including effects on endothelial cell function, lipoprotein oxidation, cytokine levels and on hemostasis. [5][6][7][8][9][10] These cellular responses to exogenous estrogen are consistent with the efficacy of estrogens in preclinical models of atherosclerosis, including the cholesterol-fed rabbit 11 and the apoE knockout mouse. 12 In contrast to the beneficial effects of exogenous estrogens in murine apoE KO and apoE2 transgenic animals, 13 highdose estrogen increases apoB and VLDL synthesis in rats 14,15 and increases total cholesterol in some mouse strains, 16,17 while decreasing cholesterol in others.…”

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confidence: 65%

Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

Zuckerman

Evans

Schelm

et al. 1999

ATVB

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Abstract-The murine double transgenic mouse expressing both human apoB100 and cholesteryl ester transfer protein (CETP), has been used as a model to understand the effects mediated by various therapeutic modalities on serum lipoproteins and on atherosclerotic lesion progression. In the present study the effects of estrogen therapy on serum lipoproteins were investigated after mice were placed on an atherosclerotic diet. The daily oral administration of 20 or 100 g/kg of 17 ␣-ethinyl estradiol resulted in a significant, dose-dependent increase in LDL cholesterol over a 20-week regimen. These differences were apparent by 6 weeks and further increases were observed through the 20-week period. Although CETP did result in a reduction in total HDL, estrogen did not have any impact on the amount of CETP activity associated with the HDL particles. The significant increase in LDL cholesterol was associated with increases in the amount of apoB100 and B48 and apoE-containing particles. Hepatic apoB message levels, however, were not different between the experimental groups. Although the extent of atherosclerotic lesions was modest, Ͻ0.5% of the aortic surface area in the vehicle group, the high-dose estrogen group, showed an increase in lesion area consistent with the elevation in LDL cholesterol. These lesions, primarily restricted to the aortic root and aortic semilunar valves, were more intensely stained with Oil Red O in the high-dose estrogen group when compared with the vehicle controls. (Arterioscler Thromb

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confidence: 65%

Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

Zuckerman

Evans

Schelm

et al. 1999

ATVB

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“…2, 17, and 18). The direct effects of E2 on the vasculature include rapid effects on vasomotor tone (19)(20)(21)(22), and longer-term effects on atherosclerosis (3,4,17,18,(23)(24)(25)(26) and vascular cell proliferation and migration (17,18,(27)(28)(29)(30)(31)(32). The longer-term effects of estrogens result from alterations in gene expression, and are believed to be mediated by estrogen receptors, which are ligand-activated transcription factors (33,34).…”

Section: Discussionmentioning

confidence: 99%

Estrogen inhibits the vascular injury response in estrogen receptor β-deficient female mice

Karas

Hodgin

Kwoun

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

240

129

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The protective effects of estrogen in the cardiovascular system result from both systemic effects and direct actions of the hormone on the vasculature. Two estrogen receptors have been identified, ER␣ and ER␤. We demonstrated previously that estrogen inhibits the response to vascular injury in both wild-type and ER␣-deficient mice, and that ER␤ is expressed in the blood vessels of each, suggesting a role for ER␤ in the vascular protective effects of estrogen. In the present study, we examined the effect of estrogen administration on mouse carotid arterial injury in ER␤-deficient mice. Surprisingly, in ovariectomized female wild-type and ER␤ knockout mice, 17␤-estradiol markedly and equally inhibited the increase in vascular medial area and the proliferation of vascular smooth muscle cells after vascular injury. These data demonstrate that ER␤ is not required for estrogenmediated inhibition of the response to vascular injury, and suggest that either of the two known estrogen receptors is sufficient to protect against vascular injury, or that another unidentified estrogen receptor mediates the vascular protective effects of estrogen.17␤-estradiol ͉ vascular smooth muscle T he cardiovascular protective effects of estrogen are well established, and the direct effects of the hormone on vascular tissues are now well recognized (1, 2). Using a model of carotid arterial injury in a mouse, we have shown previously that administration of physiologic levels of 17␤-estradiol (E2) completely inhibits the vascular injury response in ovariectomized female wild-type (w.t.) mice (3,4). Subsequent studies demonstrated that E2 continues to protect against vascular injury in ER␣ knockout mice (␣ERKO) (4), indicating that estrogen can inhibit the vascular injury response by an ER␣-independent pathway. Another estrogen receptor, termed ER␤, was identified recently (5), suggesting the possibility that ER␤ mediates the protective effects of E2 on the vasculature. Studies demonstrating that ER␤ is expressed in vascular cells and tissues (4, 6-11), and, in contrast to ER␣, that ER␤ mRNA expression increases in vascular endothelial and smooth muscle cells after vascular injury (11, 12), prompted widespread speculation that ER␤ may place a central role in mediating the cardiovascular effects of E2 (10,13,14). To test directly the hypothesis that ER␤ mediates the vasoprotective effects of estrogen, we have now developed knockout mice in which the ER␤ gene is disrupted by gene targeting (␤ERKO) (15). In the present study, we examine the effect of estrogen on the response to vascular injury in these ␤ERKO mice. MethodsAnimals. The ␤ERKO mice were generated by targeted disruption of exon three of the ER␤ gene as described (15). The ␤ERKO mice are normal in appearance, but the females are subfertile because of impaired ovarian function (15). For vascular injury studies, 3-to 4-month-old F 2 littermates bred from heterozygote matings of F 1 animals (129 ϫ C57BL͞6J) were used. The mice were fed a normal diet ad libitum, as previously described (3...

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“…Estrogen seems able to inhibit cholesterol accumulation and intimal hyperplasia, independent of changes in plasma lipoproteins in ovariectomized cynomolgus monkeys and rabbits fed an atherogenic diet. [21][22][23] Suppression of the arterial uptake and/or degradation of LDL by estrogen may explain these effects. 23 However, these mechanisms are not able to work when the endothelial cell layer is seriously damaged.…”

Section: Discussionmentioning

confidence: 99%

“…18 -20 Furthermore, estrogen was able to inhibit cholesterol accumulation in the aorta as well as in the coronary arteries of cholesterol-fed rabbits and monkeys, and this was partly explained by suppression of the arterial uptake and/or degradation of LDL. 16,[21][22][23] Whereas the direct antiatherogenic effect of estrogen per se on the vessel wall is poorly understood, interest has focused on the role of nitric oxide (NO) because NO has antiatherosclerotic effects such as inhibition of monocyte adherence to endothelial cells; inhibition of smooth muscle cell chemotaxis, proliferation, and relaxation; and inhibition of platelet aggregation. 24 -27 Estrogen has also been shown to increase endothelial NO synthase (eNOS) protein and activity and NO production by receptor-mediated mechanisms in cultured endothelial cells.…”

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confidence: 99%

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

Hayashi

Esaki

Muto

et al. 2000

ATVB

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Abstract-Dehydroepiandrosterone (DHEA) is speculated to have an antiatherosclerotic effect, although the mechanism of action remains unclear. The objective of the current study was to determine whether the antiatherosclerotic effect of DHEA is related to its conversion to estrogen and to define the role of nitric oxide (NO) in the antiatherosclerotic effect of DHEA. Forty-eight oophorectomized rabbits were divided into 5 groups and fed the following diets for 10 weeks: group 1, a regular rabbit diet plus 1% cholesterol (a high-cholesterol diet [HCD]); group 2, an HCD plus 0.3% DHEA; group 3, an HCD plus 0.3% DHEA and fadrozole (2.0 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), a specific aromatase inhibitor; group 4, an HCD plus 17␤-estradiol (20 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ); and group 5, a regular diet. Atherosclerotic lesions, lipid deposition in aortic vessels, and basal and stimulated NO release were measured in the aforementioned groups of rabbits. NO release was measured by using an NO-selective electrode as well as by measuring vascular responses and the plasma NO metabolites nitrite and nitrate. The plasma total cholesterol level was increased, but there were no significant differences in lipid profile in the 4 groups of rabbits that were fed the HCD. The area occupied by atherosclerosis in the thoracic aorta was diminished by Ϸ60% in the DHEA-treated rabbits (group 2) compared with the HCD group of rabbits (group 1); there was a corresponding 80% decrease in the estradiol group (group 4) but only a 30% decrease in the DHEA plus fadrozole group (group 3). In the aortas of rabbits from groups 1 and 3, the acetylcholine-induced and tone-related basal NO-mediated relaxations were diminished compared with those of the controls (group 5). However, these relaxations were restored in the aortas of group 2 and 4 rabbits, and an increase in NO release was observed in groups 2 and 4 compared with groups 1 and 3, as measured by an NO-selective electrode. Injection of neither solvent (20% ethanol/distilled water) nor fadrozole significantly affected the atherosclerotic area or the NO-related responses described above. We conclude that Ϸ50% of the total antiatherosclerotic effect of DHEA was achieved through the conversion of DHEA to estrogen. NO may also play a role in the antiatherosclerotic effect of DHEA and 17␤-estradiol. have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEA-S serves as a reservoir for DHEA, since various tissues have been shown to contain steroid sulfatases. 1 The peak plasma levels of DHEA and DHEA-S occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95% around the age of 85 years. Epidemiological evidence has shown that adult men with high plasma DHEA-S levels are less likely to die of cardiovascular disease. 2 A study indicated that administration of DHEA reduced aortic fatty streak formation and cholesterol accumulation by Ϸ30% to 40% in cholesterol-fed rabbits. 3 Another report has shown a 50% reduction...

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Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits.

Cited by 199 publications

References 27 publications

Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

Estrogen inhibits the vascular injury response in estrogen receptor β-deficient female mice

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

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