Transplantation of monocyte CC-chemokine receptor 2-deficient bone marrow into ApoE3-Leiden mice inhibits atherogenesis.
OBJECTIVE
To determine the role of leukocyte CC-chemokine receptor 2 (CCR2) in the early development of atherosclerosis


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+/-1.94x10(4) microm2 compared with 20.94+/-12.71x10(4) microm2, 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).


CONCLUSIONS
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.
Guo
Jian
J
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, PO Box 9502, 2300 RA Leiden, The Netherlands. j.guo@chem.leidenuniv.nl
Van Eck
Miranda
M
Twisk
Jaap
J
Maeda
Nobuyo
N
Benson
G Martin
GM
Groot
Pieter H E
PH
Van Berkel
Theo J C
TJ
D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000502:physiology*; D002452:Cell Count; D002784:Cholesterol / Q000097:blood; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency*; D014280:Triglycerides / Q000097:blood
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014280:Triglycerides; C052720:apolipoprotein E3 (Leidein); D002784:Cholesterol