Abstract
Low density lipoprotein (LDL) receptor-deficient (LDLR–/–) mice consuming a high fat diet were used to assess the effect of endogenous and exogenous estradiol (E2) on atherosclerosis. Sexually mature female mice were ovariectomized (OVX) and implanted with subcutaneous, slow-release pellets designed to release 6 μg/day of exogenous 17β-estradiol (17β-E2), 17α-estradiol (17α-E2), or placebo (E2-deficient). Sham-operated control female (endogenous E2) and male mice were studied as controls. Aortic atherosclerotic lesion area was reduced by physiologic amounts of both endogenous and exogenous E2 compared to E2-deficient female mice. Although plasma cholesterol levels were reduced by exogenous E2 despite the absence of the LDL receptor, endogenous E2 was not associated with any cholesterol changes. In contrast, only 17α-E2 was associated with decreased fasting triglyceride. In subgroup analyses matched for time-averaged plasma total cholesterol, aortic lesion area was reduced by the presence of estradiol (E2). E2 protected LDLR–/– female mice from atherosclerosis and this protection was independent of changes in plasma cholesterol levels.—Marsh, M. M., V. R. Walker, L. K. Curtiss, and C. L. Banka. Protection against atherosclerosis by estrogen is independent of plasma cholesterol levels in LDL receptor-deficient mice. J. Lipid Res. 1999. 40: 893–900.
Highlights
Low density lipoprotein (LDL) receptor-deficient (LDLR؊/؊) mice consuming a high fat diet were used to assess the effect of endogenous and exogenous estradiol (E2) on atherosclerosis
This study evaluates the effects of estrogen on atherosclerosis that are independent of its effects on plasma cholesterol levels and establishes a new menopausal mouse model of atherosclerosis
Results were expressed as mean Ϯ SEM for all values. a P Ͻ 0.002 E2-deficient compared with endogenous and exogenous E2 (17- and 17␣-E2). b P Ͻ 0.0001 male compared with endogenous and exogenous E2 (17- and 17␣-E2). c P Ͻ 0.006 endogenous E2 compared with exogenous E2 and E2deficient. d P Ͻ 0.006 exogenous 17-E2 compared with endogenous E2, exogenous 17␣-E2, and E2-deficient. e P Ͻ 0.004 exogenous 17␣-E2 compared with endogenous E2, exogenous 17-E2, and E2-deficient. f P Ͻ 0.002 E2-deficient compared with endogenous E2 and exogenous E2 (17- and 17␣-E2)
Summary
Low density lipoprotein (LDL) receptor-deficient (LDLR؊/؊) mice consuming a high fat diet were used to assess the effect of endogenous and exogenous estradiol (E2) on atherosclerosis. Fasting plasma cholesterol was reduced by exogenous E2, both 17- and 17␣-E2 (P Ͻ 0.002), compared to E2-deficient female mice, despite the absence of the LDL receptor. Fasting plasma cholesterol was higher in endogenous E2 and E2deficient female mice (P Ͻ 0.0002) compared with male mice and did not differ between exogenous E2 female and male mice.
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