QUANTITATIVE ASSESSMENT OF AORTIC ATHEROSCLEROSIS IN APOE-ASTERISK-3 LEIDEN TRANSGENIC MICE AND ITS RELATIONSHIP TO SERUM-CHOLESTEROL EXPOSURE

Transgenic mice overexpressing the human dysfunctional apolipoprotein E variant, APOE3 Leiden, develop hyperlipidemia and are highly suscep tible to diet-induced atherosclerosis. In the present study, we invest igated the effects of diet composition and feeding period on serum cho lesterol exposure and the amount of atherosclerosis in the aortic sinu s in these mice, using quantitative image analysis. On each of the thr ee diets tested-a low-fat diet, a high-saturated-fat/cholesterol diet, and a high saturated-fat/high-cholesterol/0.5%-cholate diet-transgeni c animals showed a marked hyperlipidemia compared with nontransgenic l ittermates. Measurement of the atherosclerotic lesion areas in cross s ections of the aortic sinus in animals exposed to these three diets fo r up to 6 months showed a 5 to 10 times greater lesion area in transge nic mice compared with nontransgenic controls. Highly significant posi tive correlations were found between the log-transformed data on lesio n area and serum cholesterol exposure (r=.82 to .85 for the 1-, 2- and 3-month treatment groups), indicating that the hyperlipidemia is like ly to be a major determinant in lesion formation. On the basis of thes e findings, we suggest that the APOE3 Leiden mouse represents a promi sing model for intervention studies with hypolipidemic and antiatheros clerotic drugs.