SUSCEPTIBILITY TO DIET-INDUCED ATHEROSCLEROSIS IN TRANSGENIC MICE EXPRESSING A DYSFUNCTIONAL HUMAN APOLIPOPROTEIN E(ARG 112,CYS142)

Transgenic mice expressing apolipoprotein (ape) E(Cys 142), a human de fective variant of apo E, have elevated levers of plasma cholesterol, triglycerides, and very-low-density lipoproteins (VLDL); beta-VLDL, th e biochemical hallmark of the human genetic disease type III hyperlipo proteinemia (HLP), is also present in these mice. This study was desig ned to determine whether these type III HLP mice have an increased sus ceptibility to spontaneous or diet-induced atherosclerosis. Three 4-mo nth-old male transgenic mice and three male nontransgenic littermates were assessed for the presence of atherosclerotic lesions in the proxi mal aorta. No lipid-stained microscopic lesions were visible in the ao rtas of nontransgenic mice, whereas minimal lesions were observed on t he aortic valve stumps of transgenic mice. To magnify the effect of th e mutant ape E on the susceptibility of the transgenic animals to athe rosclerosis, 8 transgenic and 8 nontransgenic mice were fed a syntheti c diet containing 1% cholesterol, 16% fat, and 0.5% cholic acid for 3 months. The diet induced an increase in plasma cholesterol level in bo th transgenic and nontransgenic mice. However, the increase in plasma cholesterol level in the transgenic mice was all in the VLDL fraction, whereas in nontransgenic mice it was due to increases in both VLDL an d high-density lipoprotein (HDL) fractions. Plasma triglyceride levels fell in both groups of mice. After 3 months on the diet, there were c ompositional changes in the VLDL of both groups, characterized mainly by higher cholesteryl ester content, that resulted in beta-migration o n agarose gel electrophoresis. Despite similar VLDL lipid compositions , the extent of atherosclerosis differed markedly in the two groups. N ontransgenic mice had small lesions localized only to the aortic valve stumps, whereas transgenic mice had complicated lesions with high cel lularity and fibrous caps on both the valve stumps and the aortic wall . These results indicate that the abnormal lipoprotein that accumulate s in the plasma of apo E(Cys142) mice has a strong atherogenic potenti al, and support the hypothesis that beta-VLDL is responsible for the d evelopment of atherosclerosis in type III HLP.