Susceptibility to diet-induced atherosclerosis in transgenic mice expressing a dysfunctional human apolipoprotein E(Arg 112,Cys142)

Transgenic mice expressing apolipoprotein (apo) E(Cys 142), a human defective variant of apo E, have elevated levels of plasma cholesterol, triglycerides, and very-low-density lipoproteins (VLDL); β-VLDL, the biochemical hallmark of the human genetic disease type III hyperlipoproteinemia (HLP), is also present in these mice. This study was designed to determine whether these type III HLP mice have an increased susceptibility to spontaneous or diet-induced atherosclerosis. Three 4- month-old male transgenic mice and three male nontransgenic littermates were assessed for the presence of atherosclerotic lesions in the proximal aorta. No lipid-stained microscopic lesions were visible in the aortas of nontransgenic mice, whereas minimal lesions were observed on the aortic valve stumps of transgenic mice. To magnify the effect of the mutant apo E on the susceptibility of the transgenic animals to atherosclerosis, 8 transgenic and 8 nontransgenic mice were fed a synthetic diet containing 1% cholesterol, 16% fat, and 0.5% cholic acid for 3 months. The diet induced an increase in plasma cholesterol level in both 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 and high-density lipoprotein (HDL) fractions. Plasma triglyceride levels fell in both groups of mice. After 3 months on the diet, there were compositional changes in the VLDL of both groups, characterized mainly by higher cholesteryl ester content, that resulted in β-migration on agarose gel electrophoresis. Despite similar VLDL lipid compositions, the extent of atherosclerosis differed markedly in the two groups. Nontransgenic mice had small lesions localized only to the aortic valve stumps, whereas transgenic mice had complicated lesions with high cellularity and fibrous caps on both the valve stumps and the aortic wall. These results indicate that the abnormal lipoprotein that accumulates in the plasma of apo E(Cys142) mice has a strong atherogenic potential, and support the hypothesis that β-VLDL is responsible for the development of atherosclerosis in type III HLP.