Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E.

Abstract

To develop a murine model system to test the role of monocyte-derived macrophages in atherosclerosis, the osteopetrotic (op) mutation in the macrophage colonystimulating factor gene was bred onto the apolipoprotein E (apoE)-deficient background. The doubly mutant (op/apoEdeficient) mice fed a low-fat chow diet had significantly smaller proximal aortic lesions at an earlier stage of progression than their apoE-deficient control littermates. These lesions in the doubly mutant mice were composed of macrophage foam cells. The op/apoE-deficient mice also had decreased body weights, decreased blood monocyte differentials, and increased mean cholesterol levels of 41300 mg/dl. Statistical analysis determined that atherosclerosis lesion area was significantly affected by the op genotype and gender. The confounding variables of body weight, plasma cholesterol, and monocyte differential, which were all affected by op genotype, had no significant additional effect on lesion area once they were adjusted for the effects of op genotype and gender.

The emergence of mouse models of atherosclerosis and their relevance to clinical research

“…This finding confirms the hypolipidaemic effect of M-CSF that had been observed in humans, primates, and rabbits [50][51][52]. However, these apoE-deficient op mice had paradoxically fourto 10-fold smaller aortic root lesions than their controls [45]. Thus, this study proves the proatherogenic role of monocyte-derived macrophages, as fewer monocyte-macrophages led to smaller lesions despite higher levels of proatherogenic lipoprotein particles.…”

“…The apoE-deficient op mice had plasma cholesterol levels approximately 2.5-fold higher than their apoE deficient littermate controls, the increase occurring in the atherogenic VLDL ϩ LDL fractions [45]. This finding confirms the hypolipidaemic effect of M-CSF that had been observed in humans, primates, and rabbits [50][51][52].…”

“…1. The lesions of the apoE-deficient mouse also contain the same types of cells seen in human lesions: macrophages, T-cells, and smooth muscle cells [41,[44][45][46]. In contrast to diet-induced atherosclerosis in mice in which lesions are largely limited to the aortic root, lesions in apoE-deficient mice form throughout the arterial tree with similar sites of predilection -as seen in human atherosclerosis -at the aortic root, lesser curvature of the arch, proximal coronary arteries, and at branch points [19,39,40,41,47,48].…”

“…The importance of monocyte-macrophages in atherogenesis was confirmed by breeding apoE-deficient mice with osteopetrotic (op) mice, a mutant mouse line deficient in the monocyte-macrophage cytokine M-CSF [45]. The apoE-deficient op mice had plasma cholesterol levels approximately 2.5-fold higher than their apoE deficient littermate controls, the increase occurring in the atherogenic VLDL ϩ LDL fractions [45].…”

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

“…10 Macrophages, participating in both lipid metabolism and inflammation, are intimately involved in all phases of atherosclerosis, from development of the fatty streak to processes that ultimately contribute to plaque rupture and myocardial infarction. 11 Macrophage expression of certain genes is atheroprotective, whereas inadequate expression or lack of expression of these same genes in macrophages increases atherosclerosis. 12 It has been reported that macrophage LXRa is required for antiatherogenic activity of LXRa agonists.…”