Repopulation of apolipoprotein E knockout mice with CCR2-deficient bone marrow progenitor cells does not inhibit ongoing atherosclerotic lesion development.
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.


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+/-1.06x10(5) microm2. At 9 weeks after transplantation, apoE-/---> apoE-/- and apoE-/-/CCR2-/---> apoE-/- mice had developed significantly larger atherosclerotic lesions (4.49+/-0.92x10(5) microm2, P<0.02 and 4.15+/-0.62x10(5) microm2, 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.


CONCLUSIONS
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.
Guo
Jian
J
Division of Biopharmaceutics, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.
de Waard
Vivian
V
Van Eck
Miranda
M
Hildebrand
Reeni B
RB
van Wanrooij
Eva J A
EJ
Kuiper
Johan
J
Maeda
Nobuyo
N
Benson
G Martin
GM
Groot
Pieter H E
PH
Van Berkel
Theo J C
TJ
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D011828:Radiation Chimera; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D013864:Thioglycolates / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D013864:Thioglycolates; D014280:Triglycerides; D003094:Collagen; D002784:Cholesterol