on October 12, 2006
Published online before print October 12, 2006, doi: 10.1161/01.ATV.0000249641.96896.e6
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Submitted on January 4, 2006
Accepted on September 14, 2006
Macrophage Low-Density Lipoprotein Receptor-Related Protein Deficiency Enhances Atherosclerosis in ApoE/LDLR Double Knockout Mice
L. Hu ;
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 (J.T.T.), Department of Heamatology, LUMC, Leiden, The Netherlands.
* To whom correspondence should be addressed. 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.
Key words: atherosclerosis • collagen • genetically altered mice • LRP • macrophage
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