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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:447.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Transplantation of Monocyte CC-Chemokine Receptor 2–Deficient Bone Marrow Into ApoE3–Leiden Mice Inhibits Atherogenesis

Jian Guo; Miranda Van Eck; Jaap Twisk; Nobuyo Maeda; G. Martin Benson; Pieter H.E. Groot; Theo J.C. Van Berkel

From the Division of Biopharmaceutics (J.G., M.V.E., J.T., T.J.C.V.B.), Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands; Department of Pathology and Laboratory Medicine (N.M.), University of North Carolina Medical School, Chapel Hill, NC; and Atherosclerosis Department (G.M.B., P.H.E.G.), GlaxoSmithKline Pharmaceuticals, Stevenage, UK.

Correspondence to Jian Guo, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (LACDR), Gorlaeus Laboratories, Leiden University, Einsteinweg 55, PO Box 9502, 2300 RA Leiden, The Netherlands. E-mail j.guo{at}chem.leidenuniv.nl

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±1.94x10⁴ µm² compared with 20.94±12.71x10⁴ 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.

Key Words: atherosclerosis • chemokines • bone marrow transplantation • transgenic animals

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