Estrogen-mediated increases in LDL, cholesterol and foam cell-containing lesions in human ApoB100 x CETP transgenic mice

The murine double transgenic mouse expressing both human apoB100 and choles teryl ester transfer protein (CETP), has been used as a model to understand the effects mediated by various therapeutic modalities on serum lipoprotei ns and on atherosclerotic lesion progression. In the present study the effe cts of estrogen therapy on serum lipoproteins were investigated after mice were placed on an atherosclerotic diet. The daily oral administration of 20 or 100 mu g/kg of 17 alpha-ethinyl estradiol resulted in a significant, do se-dependent increase in LDL cholesterol over a 20-week regimen. These diff erences were apparent by 6 weeks and further increases were observed throug h 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 as sociated with increases in the amount of apoB100 and B48 and apoE-containin g particles. Hepatic apoB message levels, however, were not different betwe en the experimental groups. Although the extent of atherosclerotic lesions was modest, <0.5% 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 a ortic root and aortic semilunar valves, were more intensely stained with Oi l Red O in the high-dose estrogen group when compared with the vehicle cont rols.