Estrogen-mediated increases in LDL cholesterol and foam cell-containing lesions in human ApoB100xCETP transgenic mice.
The murine double transgenic mouse expressing both human apoB100 and cholesteryl ester transfer protein (CETP), has been used as a model to understand the effects mediated by various therapeutic modalities on serum lipoproteins and on atherosclerotic lesion progression. In the present study the effects of estrogen therapy on serum lipoproteins were investigated after mice were placed on an atherosclerotic diet. The daily oral administration of 20 or 100 microg/kg of 17 alpha-ethinyl estradiol resulted in a significant, dose-dependent increase in LDL cholesterol over a 20-week regimen. These differences were apparent by 6 weeks and further increases were observed through 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 associated with increases in the amount of apoB100 and B48 and apoE-containing particles. Hepatic apoB message levels, however, were not different between 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 aortic root and aortic semilunar valves, were more intensely stained with Oil Red O in the high-dose estrogen group when compared with the vehicle controls.
Zuckerman
S H
SH
Division of Cardiovascular Research, Lilly Research Labs, DC0434, Indianapolis, Ind 46285, USA. Zuckerman_Steven@Lilly.com
Evans
G F
GF
Schelm
J A
JA
Eacho
P I
PI
Sandusky
G
G
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000502:physiology*; D001161:Arteriosclerosis / Q000517:prevention & control; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects / Q000473:pathology; D006023:Glycoproteins; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D004967:Estrogens; D006023:Glycoproteins