Anatomical differences and atherosclerosis in apolipoprotein E-deficient mice with 129/SvEv and C57BL/6 genetic backgrounds

Abstract

There are well-known genetic background effects on atherosclerosis susceptibility in mice. To study the basis of these effects, we have generated the apolipoprotein E-null mutation in mouse embryonic stem cells of 129/SvEv origin, maintained it in the inbred strain (129-apoE), and compared these mice with those previously made in strain 129/Ola and backcrossed to a C57BL/6 genetic background (B6-apoE). Plasma cholesterol and triglyceride levels in the apoE-129 mice are twice the levels in apoE-B6, and both VLDL/chylomicron remnants and HDL particles are increased. Regression analysis of plaque size relative to the age of mice suggests that the initiation of atherosclerotic plaque development at the aortic root is slower in 129-apoE mice (intercept at 3.9 mo in females and 4.1 mo in males) than in B6-apoE mice (1.3 mo in females and 2.8 mo in males). In contrast, 129-apoE mice develop extensive plaques in the aortic arches earlier than B6-apoE mice. Distinct differences in the geometry of the aortic arch between the two strains suggest that anatomical differences may contribute to the effects of genetic background on atherosclerosis. The 129-apoE/B6-apoE pair thus provides a tool to study factors governing the relation between arterial geometry and the location of plaque development. Keywordsanimal model; atherosclerotic plaque distribution; cholesterol; aortic arch; aortic root; inbred mouse strain; ductus arteriosus Well-characterized animal models are essential for the study of common human diseases such as those involving the cardiovascular system. The first practical mouse model of atherosclerosis was developed by inactivating the gene coding for apolipoprotein E (apoE) (1-3). ApoE plays a central role in lipoprotein metabolism and is required for efficient receptor-mediated plasma clearance by the liver of chylomicron remnants and very low-density lipoprotein (VLDL)-remnant particles (4). Lack of apoE in the mutant mice results in an increased accumulation of cholesterol-enriched remnant particles and four times normal plasma cholesterol levels even Correspondence to: Dr. Nobuyo Maeda, Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. Phone: 919-966-6912, Fax: 919-966-8800. E-mail: nobuyo@med.unc.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. when the mice are fed regular low-fat, low-cholesterol chow. The apoE-deficient mice spontaneously develop atherosclerotic plaques similar to those seen in humans (5,6), with the exception that the spontaneo...

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