Induction of Atherosclerosis by Low-Fat, Semisynthetic Diets in LDL Receptor–Deficient C57BL/6J and FVB/NJ Mice

OBJECTIVE: A semisynthetic diet with varying amounts of cholesterol was used to achieve hypercholesterolemia and atherosclerosis in LDL receptor-deficient (LDLR-/-) mice. Atherosclerotic lesions were measured as cross-sectional area at the aortic root and brachiocephalic artery and by en face analysis of aortic lesion area in 209 male and female animals on the C57BL/6J (B6.LDLR-/-) and FVB/NJ (FVB.LDLR-/-) backgrounds. METHODS AND RESULTS: The semisynthetic diet containing 4.3% fat and 0.00% or 0.02% cholesterol was sufficient to induce hypercholesterolemia (12.6+/-2.4 mmol/L) and atherosclerosis in B6.LDLR-/- mice at the aortic root (98,980+/-37 727 microm2) and brachiocephalic artery (12,039+/-12,750 microm2) but did not produce significant lesions in the aorta measurable by the en face method. Raising dietary cholesterol to 0.15%, 0.30%, or 0.50% more than doubled plasma cholesterol levels (35.9+/-8.5 mmol/L) and resulted in significant en face lesions. It also led to a significant increase in atherosclerotic lesion area at the aortic root (547,753+/-182,151 microm2) and brachiocephalic arteries (125,666+/-59,339 microm2). Although FVB.LDLR-/- mice developed comparable cholesterol levels, they were relatively atherosclerosis resistant and had many-fold smaller lesions. CONCLUSIONS: These results should aid investigations of atherosclerosis in LDLR-/- mice by informing the selection of diet to be used and the location of lesions to be scored.