Murine Models of Atherosclerosis

The induction of diet-induced atherosclerosis is generally difficult in rodent species that have low LDL and VLDL plasma concentrations. Mice and rats carry most of their cholesterol in atheroprotective HDL particles and are naturally deficient in CETP.16 Low VLDL and LDL plasma concentrations in mice are maintained by an avid uptake and catabolism via the LDLr. Two strains of genetic knockout mice can overcome this limitation. Specific murine knockout strains have been developed for either the LDLr (LDLr_/_) or apoE (apoE _/_) that impede uptake by the LDLr and induce higher LDLc and lower HDLc plasma concentrations in mice closer to human levels. However, higher plasma concentrations of VLDLc and LDLc are observed in apoE _/_ mice than in apoE-deficient humans. As a result, these knockouts are susceptible to atherosclerosis induced by high-fat, cholesterol-enriched diets and provide a reliable short-term animal model for this disease. While drug-induced changes in LDLc plasma concentrations can be detected almost immediately in these models, alterations in foam cell and plaque progression generally require multiple (4-12) weeks of dosing.32 Similar effects on HDLc lowering, LDLc increases, and cholesterol-induced atherosclerosis progression have been observed in transgenic mice overexpressing human CETP either alone in wild-type mice or on a LDLr _/_ or apoE _/_ genetic background.16

Both LDLr_/_ and apoE _/_ models have been further exploited by backcrossing with other knockouts or transgenic mice overexpressing specific proteins to create new transgenic models that have helped define many of the mechanistic components underlying this disease. As a result, the specific effects of both human proinflammatory, anti-inflammatory, oxidative, antioxidant, and redox-regulated proteins on the atherosclerotic process have been confirmed in animal studies.

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