These studies use genetically modified mice to study the effects of candidate compounds on lipoprotein levels and atherosclerosis. Good models of atherosclerosis are very difficult to find, as most laboratory animals are resistant to the development of lesion development. The usual model is the cholesterol-fed rabbit. This model produces significant disease, characterized by excessive cholesterol accumulation. Another often used model involves a balloon injury to the entire aorta of cholesterol fed rats. These lesions have more of a smooth muscle cell component to them. Both models suffer from significant disadvantages. Rabbits are large animals and the amount of compound necessary to treat large numbers of animals is prohibitive. The lipid rich lesions are very aggressive and are difficult to treat. Additionally, once the lesions have formed and the animals are returned to a chow diet, the lesions actually progress for a period of time before resolving. The ballooned rat model was meant to study platelet involvement in lesion development. As it turns out, the insult created by ballooning the aorta is so great that it is very difficult to alter these lesions as well. The mouse is usually resistant to the development of atherosclerosis, although some strains develop mild disease when fed diets high in cholesterol and cholate. The advent of mutant mice has resulted in the ability to induce disease of varying severity in a small animal over a reasonably short period of time.

Varying degrees of hypercholesterolemia and hypertriglyceridemia. Development of macrophage foam cell lesions beginning at the level of the aortic sinus and developing throughout the vascular tree. Lesion severity is modulated by the genetic mutation, diet and length of study. Some investigators have found plaque rupture after prolonged feeding.

Atherosclerosis studies utilize genetically modified mice, e.g. Apo E deficient, LDL Receptor deficient or Apo B transgenic animals. Basic studies involve feeding a diet containing high fat and 0.2% cholesterol for a period of 8 – 12 weeks. Treatment can begin at the onset of feeding, or after an 8 week pre-feed period. These designs are for lesion progression and lesion regression studies, respectively.

Serum cholesterol, triglycerides and lipoprotein distribution. Histological examination of the brachial cephalic artery (BCA) or aortic sinus with an estimation, by image analysis, of lesion area and macrophage area, as well as lesion characterization.