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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2710.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Macrophage Low-Density Lipoprotein Receptor-Related Protein Deficiency Enhances Atherosclerosis in ApoE/LDLR Double Knockout Mice

L. Hu; L.S.M. Boesten; P. May; J. Herz; N. Bovenschen; M.V. Huisman; J.F.P. Berbée; L.M. Havekes; B.J.M. van Vlijmen; J.T. Tamsma

From the Vascular Medicine Unit (L.H., L.S.M.B., M.V.H., L.M.H., J.T.T.), Department of General Internal Medicine, LUMC, Leiden, The Netherlands; TNO-Quality of Life (L.S.M.B., L.M.H.), Gaubius Laboratory, Leiden, The Netherlands; Zentrum für Neurowissenschaften/Medizinische Klinik II (P.M.), Universität Freiburg, Freiburg, Germany, Department of Molecular Genetics (J.H.), UT Southwestern, Dallas, Tex; Department of Pathology (N.B.), UMCU, Utrecht, The Netherlands; Department of Endocrinology and Metabolic Diseases (J.F.P.B.), LUMC, Leiden, The Netherlands; Haemostasis and Thrombosis Research Center (B.J.M.v.V.), Department of Heamatology, LUMC, Leiden, The Netherlands.

Correspondence to J.T. Tamsma, Vascular Medicine Unit, Department of General Internal Medicine, Leiden University Medical Center, C4-R, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail j.t.tamsma{at}lumc.nl

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.

We investigated the role of macrophage specific LRP deficiency in the development of atherosclerosis independent of its role in lipoprotein metabolism. Specific deletion of macrophage LRP in mice resulted in more advanced atherosclerosis and in lesions that contain more collagen and less relative numbers of CD3+ T cells. This indicates that macrophage LRP has an atheroprotective potential.

Key Words: atherosclerosis • collagen • genetically altered mice • LRP • macrophage

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