[Frontiers in Bioscience 2, d298-308, June 15, 1997]

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John M. Taylor and Jianglin Fan

Gladstone Institute of Cardiovascular Disease, the Department of Physiology, and the Cardiovascular Research Institute, University of California, San Francisco, CA


The finding that the cholesterol component in diets of meat, milk, and eggs resulted in atherosclerotic lesions in rabbits was made more than eighty years ago (reviewed in refs. (1, 2)), and it established the rabbit as the first experimental model for the study of this disease. In the decades following this observation, investigators demonstrated that laboratory chow supplemented with less than 2% cholesterol reproduced the effect, rapidly leading to plasma cholesterol concentrations that can exceed 2,000 mg/dl. This response could be enhanced by including up to 10% extra fat in the diet, with saturated fats increasing both circulating cholesterol levels and the extent of lesion development (summarized in ref. (3)).

The major consequence of hypercholesterolemia in the rabbit is the rapid development of atherosclerosis (1). One of the earliest events in lesion development is a focal increase in arterial concentrations of low density lipoproteins (LDL) (4). After less than two weeks on the cholesterol diet, subendothelial deposits of extracellular lipid and cytosolic lipid droplets within vascular smooth muscle cells appear (5). After just one month, fatty streaks are detected in the aorta which progress quickly to raised lesions containing macrophage-derived foam cells. During the next three to six months, these sites progress to more complex fibrous plaques that accumulate both intracellular and extracellular lipid deposits (6, 7). The plaques become advanced atheromatous lesions characterized by an extensive distribution of smooth muscle cell-derived foam cells, collagen fibers, necrotic debris, and cholesterol crystals (6, 7).

In the rabbit, lesions are distributed predominantly in the aortic arch and thoracic aorta, at the origins of intercostal arteries, and to a lesser extent in the abdominal aorta. The involvement of the intercostal ostia may be due to a higher vascular permeability of LDL and to turbulent blood flow patterns at these locations (8, 9). All lesion sites in the aorta are characterized by an increased binding of LDL to collagen and glycosaminoglycans in the vascular wall (8). The retention of lipoproteins by the extracellular matrix may facilitate their oxidative modification, thereby triggering local cellular responses that include the release of cytokines, the recruitment of lymphocytes and monocytes, expression of cell adhesion receptors, the retention of macrophages, and the migration and proliferation of smooth muscle cells (summarized in ref. (10)). These changes have been viewed as a focal response of the artery wall to local vascular injury (1, 10).

When fed to rabbits, experimental diets containing high amounts (1-2% or more) of cholesterol have resulted in lipid-laden, macrophage-enriched foamy lesions that were not typical of human atherosclerosis (1) and abundant lipid storage lesions in rabbit visceral organs (11). In humans, plaques are more abundant in the abdominal aorta, enriched in smooth muscle cells, and usually have a fibrous cap. These features led to the widely held view that rabbit atherosclerosis differed substantially from the corresponding human disease. However, recent studies that employed milder dietary regimens have demonstrated that the hypercholesterolemic rabbit can develop complex, advanced lesions that more closely resemble those found in humans (6, 7). Thus, the rabbit should continue to serve as an important model for the study of the underlying mechanisms that contribute to the development of atherosclerosis.