DECREASED ATHEROSCLEROSIS IN MICE DEFICIENT IN BOTH MACROPHAGE-COLONY-STIMULATING FACTOR (OP) AND APOLIPOPROTEIN-E

To develop a murine model system to test the role of monocyte-derived macrophages in atherosclerosis, the osteopetrotic (op) mutation in the macrophage colony-stimulating factor gene was bred onto the apolipopr otein E (apoE)-deficient background, The doubly mutant (op/apoE-defici ent) mice fed a low-fat chow diet had significantly smaller proximal a ortic lesions at an earlier stage of progression than their apoE-defic ient control littermates. These lesions in the doubly mutant mice were composed of macrophage foam cells. The op/apoE-deficient mice also ha d decreased body weights, decreased blood monocyte differentials, and increased mean cholesterol levels of approximate to 1300 mg/dl. Statis tical analysis determined that atherosclerosis lesion area was signifi cantly affected by the op genotype and gender. The confounding variabl es of body weight, plasma cholesterol, and monocyte differential, whic h were all affected by op genotype, had no significant additional effe ct on lesion area once they were adjusted for the effects of op genoty pe and gender, Unexpectedly, there was a significant inverse correlati on between plasma cholesterol acid lesion area, implying that each may be the result of a common effect of macrophage colony-stimulating fac tor levels. The data support the hypothesis that macrophage colony-sti mulating factor and its effects on macrophage development and function play a key role in atherogenesis.