Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice.

Abstract

We have studied the effects of endogenous and exogenous estrogen on atherosclerotic lesions in apolipoprotein E-deficient mice. Female mice ovariectomized (OVX) at weaning displayed increases (P < 0.01) in fatty streak lesions in the proximal aorta and aortic sinus compared with female mice with intact ovarian function. These differences between the OVX and sham controls were apparent in both chow-and "Western-type" diet-fed mice. Moreover, increases in lesion size following OVX occurred without changes in plasma cholesterol. Hormone replacement with subdermal 17-8-estradiol pellets releasing either 6, 14, or 28 jig/day significantly decreased (P < 0.001) atherosclerotic lesion area in both male and OVX female mice. In contrast, neither 17-a-estradiol (28 ,ig/day) or tamoxifen (85 ,ig/day) affected lesion progression in OVX female mice. In the Western diet-fed group, exogenous estradiol markedly reduced plasma cholesterol and triglycerides, whereas, in animals fed the chow diet, exogenous estrogen and tamoxifen treatment only decreased plasma and very low density lipoprotein triglycerides. However, lesion area was only weakly correlated with plasma cholesterol and triglycerides, 0.35 and 0.44 tau values, respectively (P < 0.01). In summary, in the apolipoprotein E-deficient mouse 17-j8-estradiol protects against atherosclerotic lesion formation, and this can only be partially explained through effects on plasma lipoprotein levels. Cardiovascular diseases resulting from atherosclerosis are a leading cause of death in Western societies (1). Epidemiological studies show men and postmenopausal women are at higher risk for such diseases than are premenopausal women, suggesting that estrogen may be cardioprotective (2, 3). This reduction in risk for cardiovascular disease is caused in part by the effects of estrogen on lipoprotein metabolism and shifts of the plasma lipoproteins to a less atherogenic profile (4). Estrogen, particularly when taken orally, lowers plasma low density lipoprotein (LDL) and raises high density lipoprotein (HDL) levels (5, 6). Although these lipoprotein changes occur in premenopausal women and postmenopausal women receiving hormone replacement therapy, in large-scale studies with adjustments for multiple risk factors, only 25-50% of the beneficial effects of estrogen appear to be due to lipoprotein effects (7).The nonlipid effects of estrogen that may contribute to the cardioprotection observed in humans include the following: effects on endothelial metabolism (8, 9), myocardial conductance, hemostatic factors (10, 11), vascular tone and reactivity (12), intimal cell proliferation (13, 14), Lp(a) levels (15), expression of adhesion molecules (16), platelet aggregation (17), LDL oxidation (18, 19), inflammatory cytokine expression (20, 21), and extracellular matrix synthesis. Additionally, estrogen might affect arterial wall calcification (22), the formation of unstable plaque and the generation of occlusive thrombi (4).Detailed systematic evaluation of these parameters in vivo requir...

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

“…The use of these well-defined transgenic models permits a systematic evaluation of the changes at the cellular and molecular level that occur within the lesion, and offers a small animal model in which pharmacologic interventions can be evaluated during the preclinical assessment of compounds that proceed to clinical trials. Using this approach, for example, the effects of estrogen, probucol and the angiotensin II receptor antagonist Losartan 12,32,36 have been evaluated in the apoE knockout, and with probucol, in the LDL receptor knockout. 32 Whereas both Losartan and pharmacologic doses of 17␤-estradiol reduced lesion size in the apoE knockout, probucol actually increased lesion size in both of these models.…”

“…[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. 18 In the latter 2 studies, chronic estrogen treatment resulted in a shift in cholesterol from HDL to a significant increase in LDL cholesterol.…”

The emergence of mouse models of atherosclerosis and their relevance to clinical research

“…Feeding a diet supplemented with 2% plant phytosterols led to decreases in both total plasma cholesterol and aortic root lesion area [56]. Subdermal 17-␤-oestradiol pellets decreased aortic root lesion area and whole aorta surface lesion area in ovariectomized apoE-deficient mice, and also decreased levels of VLDL cholesterol [57]. Adding 0.5% of an antioxidant, N,NЈ-diphenyl 1,4-phenylenediamine, to a high fat (13%) high cholesterol diet (0.15%) also resulted in decreased aortic lesion surface area, although this drug was associated with increased mortality and failure to gain normal body weight [58].…”

The AF-1 activation-function of ERα may be dispensable to mediate the effect of estradiol on endothelial NO production in mice

“…Although lipoprotein changes occur in premenopausal women and postmenopausal women receiving hormone replacement therapy, in large-scale studies with adjustments for multiple risk factors, only 25-50% of the beneficial effects of estrogen seem to be caused by lipoprotein effects (4). Several large animal species including non-human primate (5), swine (6), and rabbits (7) and, more recently, apolipoprotein E-deficient mice (8,9) have been used to assess these nonlipid effects of estrogen. They showed that effects on endothelium (10,11) may contribute to the cardioprotection observed in humans.…”