LIPID-DIET INDUCIBLE HEART ATTACK MURINE MODEL

摘要

An animal model of coronary heart disease has been developed where myocardial infarct can be induced by altering the animal's diet. In all embodiments, this animal model is a result of reduced activity of scavenger receptor class BI (SR-BI) and apolipoprotein E (apoE). In a preferred embodiment, the model is a result of crossbreeding two transgenic mouse lines: a knockout of SR- BI (SR-BI-/-) and an impaired apoE expressor (hypoE). The impaired apoE gene results in only 2-5% expression of apoE and a reduction in cholesterol homeostasis. Resulting animals are predisposed to hypercholesterolemia but can live longer than a year on a normal low fat diet. Serum plasma levels can be significantly elevated by changing the animal's diet to one containing high levels of fat and cholesterol. Within a month on a high fat, high cholesterol diet, animals develop atherosclerosis and myocardial infarction occurs. Survival depends on the nature of the diet and the conditions of animal husbandry and can typically be around 20-30 days after administration of the modified diet depending on the specific conditions. Housing the animals alone or in groups significantly affects survival of these animals on a high fat diet. Using Apoeh/hMx1-Cre mice, a cholesterol-independent role of apoE in atherosclerosis regression has been discovered. This mechanism is critical for lipid-removal from the fibrotic component of the plaque but not from the foam-cell rich layer beneath the endothelium. Analysis of B- and T-cell deficient SR-BI/apoEJRAG2 triple knockout mice established that B- and T-lymphocytes do not play a key role in the pathophysiology of this model of human disease. This animal model can be used to study mechanisms and progression of CHD as a function of diet, treatment with drugs to be screened for efficacy or undesirable side effects, and social environmental effects.