Transplantation of monocyte CC-chemokine receptor 2-deficient bone marrow into ApoE3-Leiden mice inhibits atherogenesis

Abstract

Objective - To determine the role of leukocyte CC-chemokine receptor 2 (CCR2) in the early development of atherosclerosis Methods and Results - Bone marrow cells harvested from CCR2 (-/-) and CCR2 (+/+) mice were transplanted into ApoE3-Leiden mice, a mouse strain susceptible for diet-induced atherosclerosis. Eight weeks after bone marrow transplantation, the diet of regular chow was switched to a high-cholesterol diet (1% cholesterol, 15% fat, 0.5% cholate) for another 8 weeks to induce atherosclerosis. No significant differences in serum cholesterol and triglyceride levels were observed between the CCR2 (+/+) → ApoE3-Leiden and CCR2 (-/-) → ApoE3-Leiden mice. However, the mean cross-sectional aortic root lesion area of CCR2 (-/-) → ApoE3-Leiden mice was only 2.94±1.94×104 μm2 compared with 20.94±12.71×104 μm2, for CCR2 (+/+) → ApoE3-Leiden mice. Thus, the absence of CCR2 on leukocytes induces an 86% reduction of aortic lesion area as compared with controls (n=10, P<0.01). Conclusion - These results provide direct evidence that CCR2 expressed by leukocytes plays a critical role in the initiation of early atherosclerosis and that pharmacological intervention in CCR2 function represents an attractive target to inhibit atherogenesis.