on March 17, 2005
Published online before print March 17, 2005, doi: 10.1161/01.ATV.0000163181.40896.42
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Submitted on June 22, 2004
Accepted on February 18, 2005
Repopulation of Apolipoprotein E Knockout Mice With CCR2-Deficient Bone Marrow Progenitor Cells Does Not Inhibit Ongoing Atherosclerotic Lesion Development
Jian Guo ;
From Division of Biopharmaceutics (J.G., V.d.W., M.V.E., R.B.H., E.J.A.W., J.K., 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; Atherosclerosis Department (M.B., P.H.E.G.), GlaxoSmithKline Pharmaceuticals, Stevenage, UK.
* To whom correspondence should be addressed. E-mail: t.berkel{at}chem.leidenuniv.nl.
Objective--Using bone marrow transplantation, we have previously demonstrated the critical role that hematopoietic CCR2 plays in early atherogenesis. Reconstitution of irradiated apolipoprotein (apo) E3-Leiden mice with CCR2-deficient bone marrow progenitor cells resulted in 86% reduction on overall atherosclerotic lesion development. However, no data on CCR2 in the cause of established atherosclerosis have been reported so far.
Methods and Results--To study the role of CCR2 in established atherosclerotic lesions, bone marrow progenitor cells harvested from apoE-/- and apoE-/-/CCR2-/- mice were transplanted into lethally irradiated 16-week-old apoE-/- mice with established atherosclerotic lesions. No significant differences were found in serum total cholesterol and triglycerides levels at different time points after transplantation. At age 16 weeks, lesion size in control apoE-/- mice was 3.28±1.06x105 µm2. At 9 weeks after transplantation, apoE-/-
apoE-/- and apoE-/-/CCR2-/- apoE-/- mice had significantly larger atherosclerotic lesions develop (4.49±0.92x105 µm2, P<0.02 and 4.15±0.62x105 µm2, P<0.04 compared with controls, respectively). However, no significant effect of disruption of hematopoietic CCR2 was observed on the progression of lesions. Furthermore, the macrophage positive area (78±4% versus 72±9%) and collagen content (11±6% versus 15±3%) of the lesions were similar as well.
Conclusion--In contrast to the critical role of CCR2 in the initiation of atherogenesis, bone marrow progenitor cell-derived CCR2 does not influence the progression of established atherosclerotic lesions, pointing to additional mechanisms for recruitment of monocytes at later stages of lesion development.
Key words: bone marrow transplantation • CCR2 • regression of atherosclerosis
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