Accelerating the Pace of Atherosclerosis Research

Manipulations of plasma cholesterol concentrations have been the mainstay of experimental atherosclerosis research for many decades. Before the introduction of the widespread use of genetic manipulations, atherosclerosis research primarily relied on dietary manipulations to produce hypercholesterolemic states.1 This was easily achieved in some species, such as rabbits, by the addition of cholesterol to the diet.2 Although many animals have been used in the development of atherosclerosis studies, there has been a dramatic increase in focusing on the use of mice to determine mechanisms of the disease. Like many species, mice do not readily respond to elevations of dietary cholesterol to generate a hypercholesterolemic state. The use of mice for atherosclerosis research was pioneered by the landmark studies of Dr Paigen3,4 described the appearance and quantification of lesions in the mouse aorta after mice were fed a diet containing high content of cholesterol and cholate.See accompanying article on page 50The application of mice to atherosclerosis studies was enhanced dramatically by the manipulation of genes relevant to lipoprotein metabolism. For example, mice deficient in apoE are hypercholesterolemic and develop atherosclerotic lesions even when fed normal laboratory diets.5,6 The extent of hypercholesterolemia and atherosclerosis is enhanced by feeding diets that mimic the fat contents of some fast food companies.7 Another widely used model is the low-density lipoprotein (LDL) receptor knockout mouse, and in this case, the use of a high-cholesterol/high-fat diet is required to …