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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1961.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Low Density Lipoprotein Receptor of Macrophages Facilitates Atherosclerotic Lesion Formation in C57Bl/6 Mice

Nicole Herijgers; Miranda Van Eck; Pieter H. E. Groot; Peter M. Hoogerbrugge; Theo J. C. Van Berkel

From the Division of Biopharmaceutics (N.H., M.V.E., T.J.C.V.B.), Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, Leiden, the Netherlands; the Department of Vascular Biology (P.H.E.G.), SmithKline Beecham Research and Development, Harlow, Essex, UK; and the Department of Pediatric Oncology (P.M.H.), St. Radboud University Hospital, Nijmegen, the Netherlands.

Correspondence to M. Van Eck, Division of Biopharmaceutics, Sylvius Laboratories, Leiden University, Wassenaarseweg 72, 2333 AL Leiden, Netherlands. E-mail M.Eck{at}LACDR.LeidenUniv.nl

Abstract—Macrophage-derived foam cells play an important role in the initiation and progression of atherosclerosis. To examine the role of the macrophage low density lipoprotein receptor (LDLr) in atherosclerotic lesion formation, bone marrow from LDLr knockout [LDLr(-/-)] mice was transplanted into irradiated wild-type C57Bl/6 [LDLr(+/+)] mice. After 3 months on an atherogenic diet, C57Bl/6 mice, reconstituted with LDLr(-/-) bone marrow, showed a mean lesion area of 34.7x10³±22.4x10³ µm² compared with 100.8x10³±33.0x10³ µm² (P<0.001) in control C57Bl/6 mice that were transplanted with LDLr(+/+) bone marrow. There were no significant differences in total serum cholesterol, triglyceride levels, and lipoprotein profiles between the 2 groups. Histochemical analysis of macrophage LDLr expression in the atherosclerotic lesions indicated that C57Bl/6 mice, reconstituted with LDLr(+/+) bone marrow, showed extensive staining of the foam cells in the atherosclerotic lesions, whereas mice reconstituted with LDLr(-/-) bone marrow showed only a few LDLr-positive foam cells. In vitro, peritoneal macrophages isolated from wild-type C57Bl/6 mice were, respectively, 4.7- and 10.7-fold more effective in cell association and degradation of atherogenic ¹²⁵I-ß-very low density lipoprotein than were LDLr(-/-) peritoneal macrophages, establishing that the LDLr on macrophages is important for the interaction of macrophages with ß-very low density lipoprotein. It is concluded that the LDLr on macrophages can facilitate the development of atherosclerosis, possibly by mediating the uptake of atherogenic lipoproteins.

Key Words: LDL receptor • atherosclerosis • macrophages • gene transfer

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