Title
Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis in apoE/LDLR double knockout mice
Author
Hu, L.
Boesten, L.S.M.
May, P.
Herz, J.
Bovenschen, N.
Huisman, M.V.
Berbée, J.F.P.
Havekes, L.M.
van Vlijmen, B.J.M.
Tamsma, J.T.
TNO Kwaliteit van Leven
Publication year
2006
Abstract
OBJECTIVE - In vitro studies implicate that the low-density lipoprotein receptor (LDLR)-related protein (LRP) in macrophages has a pro-atherogenic potential. In the present study, we investigated the in vivo role of macrophage specific LRP in atherogenesis independent of its role in the uptake of lipoproteins. METHODS AND RESULTS - We generated macrophage-specific LRP-deficient mice on an apoE/LDLR double-deficient background. Macrophage LRP deletion did not affect plasma cholesterol and triglyceride levels, lipoprotein distribution, and blood monocyte counts. Nevertheless, macrophage LRP deficiency resulted in a 1.8-fold increase in total atherosclerotic lesion area in the aortic root of 18-week-old mice. Moreover, LRP deficiency also resulted in a relatively higher number of advanced lesions. Whereas macrophage and smooth muscle cell content did not differ between LRP-deficient mice and control littermates, a 1.7-fold increase in collagen content and 2.3-fold decrease in relative number of CD3+ T cells were observed in lesions from macrophage specific LRP-deficient mice. CONCLUSIONS - Our data demonstrate that independent of its role in lipoprotein uptake, absence of LRP in macrophages resulted in more advanced atherosclerosis and in lesions that contained more collagen and less CD3+ T cells. In contrast to previous in vitro studies, we conclude that macrophage LRP has an atheroprotective potential and may modulate the extracellular matrix in the atherosclerotic lesions. © 2006 American Heart Association, Inc. Chemicals / CAS: cholesterol, 57-88-5; collagen, 9007-34-5; Apolipoproteins E; Collagen, 9007-34-5; LDL-Receptor Related Protein 1; Lipoproteins; Receptors, LDL
Subject
Biology
Biomedical Research
Atherosclerosis
Genetically altered mice
LRP
Macrophage
Spolipoprotein E
CD3 antigen
Aholesterol
Lipoprotein
Low density lipoprotein receptor
Triacylglycerol
Animal cell
Animal model
Animal tissue
Aorta root
Atherogenesis
Cell count
Cholesterol blood level
Control group
Controlled study
Gene deletion
In vivo study
Knockout mouse
Male
Monocyte
Mouse
Nonhuman
Observation
Protein deficiency
Protein localization
Protein transport
Smooth muscle fiber
T lymphocyte
Triacylglycerol blood level
Animals
Apolipoproteins E
Collagen
Female
Gene Expression Regulation
LDL-Receptor Related Protein 1
Lipoproteins
Macrophages
Mice
Mice, Knockout
Receptors, LDL
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DOI
https://doi.org/10.1161/01.atv.0000249641.96896.e6
TNO identifier
239625
ISSN
1079-5642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 26 (12), 2710-2715
Document type
article