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


      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 months in females and 4.1 months in males) than in B6-apoE mice (1.3 months in females and 2.8 months 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.


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        • Piedrahita J.A.
        • Zhang S.H.
        • Hagaman J.R.
        • Oliver P.M.
        • Maeda N.
        Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells.
        Proc Natl Acad Sci USA. 1992; 89: 4471-4475
        • Plump A.S.
        • Smith J.D.
        • Hayek T.
        • et al.
        Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.
        Cell. 1992; 71: 343-353
        • Zhang S.H.
        • Reddick R.L.
        • Piedrahita J.A.
        • Maeda N.
        Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.
        Science. 1992; 258: 468-471
        • Mahley R.W.
        Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.
        Science. 1988; 240: 622-630
        • Nakashima Y.
        • Plump A.S.
        • Raines E.W.
        • Breslow J.L.
        • Ross R.
        ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.
        Arterioscler Thromb. 1994; 14: 133-140
        • Reddick R.L.
        • Zhang S.H.
        • Maeda N.
        Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression.
        Arterioscler Thromb. 1994; 14: 141-147
        • Ishibashi S.
        • Goldstein J.L.
        • Brown M.S.
        • Herz J.
        • Burns D.K.
        Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.
        J Clin Invest. 1994; 93: 1885-1893
        • Knowles J.W.
        • Maeda N.
        Genetic modifiers of atherosclerosis in mice.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2336-2345
        • Hartley C.J.
        • Reddy A.K.
        • Madala S.
        • et al.
        Hemodynamic changes in apolipoprotein E-knockout mice.
        Am J Physiol Heart Circ Physiol. 2000; 279: H2326-H2334
        • Wen M.
        • Segerer S.
        • Dantas M.
        • et al.
        Renal injury in apolipoprotein E-deficient mice.
        Lab Invest. 2002; 82: 999-1006
        • McLachlan C.S.
        • Yi Xing Soh C.
        Differences in anxiety-related behavior between apolipoprotein E-deficient C57BL/6 and wild type C57BL/6 mice.
        Physiol Res. 2005; 54: 701-704
        • Van Oosten Van Oosten M.
        • Rensen P.C.
        • Van Amersfoort E.S.
        • et al.
        Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality. A new therapeutic approach to treat gram-negative sepsis.
        J Biol Chem. 2001; 276: 8820-8824
        • Vonk A.G.
        • De Bont N.
        • Netea M.G.
        • et al.
        Apolipoprotein-E-deficient mice exhibit an increased susceptibility to disseminated candidiasis.
        Med Mycol. 2004; 42: 341-348
        • Zhang S.H.
        • Reddick R.L.
        • Burkey B.
        • Maeda N.
        Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption.
        J Clin Invest. 1994; 94: 937-945
        • Knouff C.
        • Hinsdale M.E.
        • Mezdour H.
        • et al.
        Apo E structure determines VLDL clearance and atherosclerosis risk in mice.
        J Clin Invest. 1999; 103: 1579-1586
        • Paigen B.
        • Morrow A.
        • Brandon C.
        • Mitchell D.
        • Holmes P.
        Variation in susceptibility to atherosclerosis among inbred strains of mice.
        Atherosclerosis. 1985; 57: 65-73
        • Zhu H.
        • Shih J.
        • Long D.S.
        • et al.
        Characterizing 3-D geometry of mouse aortic arch using light stereo-microscopic imaging.
        in: Proceedings of the 28th IEEE EMBS Ann. Int’l Conf, New York, August–September 20062006
        • Dansky H.M.
        • Charlton S.A.
        • Sikes J.L.
        • et al.
        Genetic background determines the extent of atherosclerosis in ApoE-deficient mice.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1960-1968
        • Ishimori N.
        • Li R.
        • Kelmenson P.M.
        • et al.
        Quantitative trait loci analysis for plasma HDL–cholesterol concentrations and atherosclerosis susceptibility between inbred mouse strains C57BL/6J and 129S1/SvlmJ.
        Arterioscler Thromb Vasc Biol. 2004; 24: 161-166
        • Caro C.G.
        • Fitz-Gerald J.M.
        • Schroter R.C.
        Arterial wall shear and distribution of early atheroma in man.
        Nature. 1969; 223: 1159-1161
        • Friedman M.H.
        • Hutchins G.M.
        • Bargeron C.B.
        • Deters O.J.
        • Mark F.F.
        Correlation of human arterial morphology with hemodynamic measurements in arterial casts.
        J Biomech Eng. 1981; 103: 204-207
        • Ku D.N.
        • Giddens D.P.
        • Zarins C.K.
        • Glagov S.
        Pulsatile flow and atherosclerosis in the human carotid bifurcation.
        Arteriosclerosis. 1985; 5: 293-302
        • DeBakey M.E.
        • Lawrie G.M.
        • Gleaser D.H.
        Patterns of atherosclerosis and their surgical significance.
        Ann Surg. 1985; 201: 115-131
        • Tabibiazar R.
        • Wagner R.A.
        • Spin J.M.
        • et al.
        Mouse strain-specific differences in vascular wall gene expression and their relationship to vascular disease.
        Arterioscler Thromb Vasc Biol. 2005; 25: 302-308
        • Huang Y.
        • Guo X.
        • Kassab G.S.
        Axial nonuniformity of geometric and mechanical properties of mouse aorta is increased during postnatal growth.
        Am J Physiol Heart Circ Physiol. 2006; 290: H657-H664
        • Topouzis S.
        • Majesky M.W.
        Smooth muscle lineage diversity in the chick embryo.
        Dev Biol. 1996; 178: 430-445
        • Nguyen M.
        • Camenisch T.
        • Snouwaert J.N.
        • et al.
        The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth.
        Nature. 1997; 390: 78-81
        • Loftin C.D.
        • Trivedi D.B.
        • Tiano H.F.
        • et al.
        Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2.
        Proc Natl Acad Sci USA. 2001; 98: 1059-1064