Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:926-933
© 1996 American Heart Association, Inc.
Articles |
Quantitative Assessment of Aortic Atherosclerosis in APOE*3 Leiden Transgenic Mice and Its Relationship to Serum Cholesterol Exposure
the Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Hertfordshire, UK (P.H.E.G., G.M.B., R.S., M.V.-H.), and TNO-Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands (B.J.M. van V., M.H.H., L.M.H).
Correspondence to Pieter H.E. Groot, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn (Herts), AL6 9AR, UK. E-mail pieter_h_groot@sbphrd.com@inet.
Transgenic mice overexpressing the human dysfunctional apolipoprotein E variant, APOE*3 Leiden, develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. In the present study, we investigated the effects of diet composition and feeding period on serum cholesterol exposure and the amount of atherosclerosis in the aortic sinus in these mice, using quantitative image analysis. On each of the three diets tested—a low-fat diet, a high-saturated-fat/cholesterol diet, and a high saturated-fat/high-cholesterol/0.5%-cholate diet—transgenic animals showed a marked hyperlipidemia compared with nontransgenic littermates. Measurement of the atherosclerotic lesion areas in cross sections of the aortic sinus in animals exposed to these three diets for up to 6 months showed a 5 to 10 times greater lesion area in transgenic mice compared with nontransgenic controls. Highly significant positive correlations were found between the log-transformed data on lesion area and serum cholesterol exposure (r=.82 to .85 for the 1-, 2-, and 3-month treatment groups), indicating that the hyperlipidemia is likely to be a major determinant in lesion formation. On the basis of these findings, we suggest that the APOE*3 Leiden mouse represents a promising model for intervention studies with hypolipidemic and antiatherosclerotic drugs.
Key Words: familial dyslipoproteinemia • apolipoprotein E • diet • hyperlipidemia • animal model
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