Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption.
With the aim of establishing whether a genetically reduced capability of producing apolipoprotein E (apo E) can affect atherogenesis, we have compared the consequences of dietary stress on normal mice and on mice heterozygous or homozygous for a disrupted apo E gene. A dramatically accelerated development of lesions occurred in the vasculature of the homozygous mutants as a result of feeding an atherogenic diet for 12 wk, and extensive deposition of lipid-filled macrophages was found outside the cardiovascular system. In nine heterozygotes fed the atherogenic diet for 12 wk, the amount of apo E in their total plasma lipoproteins increased to a level comparable to normal, but all nine developed much larger foam cell lesions in their proximal aorta than those found in 3 of 9 normal mice fed the same diet. The other six normals had no lesions. Our study demonstrates that heterozygous mice with only one functional apo E gene are more susceptible to diet-induced atherosclerosis than are normal, two-copy mice. Genetically determined quantitative limitations of apo E could, therefore, have similar effects in humans when they are stressed by an atherogenic diet.
Zhang
S H
SH
Department of Pathology, School of Medicine, University of North Carolina at Chapel Hill 27599-7525.
Reddick
R L
RL
Burkey
B
B
Maeda
N
N
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001158:Arteries / Q000473:pathology*; D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004036:Diet, Atherogenic; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D012016:Reference Values; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol