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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1258.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

Inactivation of the LRP1 Intracellular NPxYxxL Motif in LDLR-Deficient Mice Enhances Postprandial Dyslipidemia and Atherosclerosis

Philip L.S.M. Gordts; Sara Reekmans; Annick Lauwers; Amber Van Dongen; Leen Verbeek; Anton J.M. Roebroek

From Experimental Mouse Genetics (P.L.S.M.G., S.R., A.L., A.V.D., L.V., A.J.M.R.), Center for Human Genetics, KU Leuven; and Experimental Mouse Genetics, Department for Molecular and Developmental Genetics (P.L.S.M.G., S.R., A.L., A.J.M.R.), VIB, Leuven, Belgium.

Correspondence to Anton J.M. Roebroek, Experimental Mouse Genetics, Center for Human Genetics, KU Leuven. Gasthuisberg O/N1. Herestraat 49, box 602, B-3000 Leuven, Belgium. E-mail anton.roebroek{at}med.kuleuven.be

Abstract

Objective— The purpose of this study was to determine the significance of the intracellular NPxYxxL motif of LRP1 for the atheroprotective role of this multifunctional receptor.

Methods and Results— LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with LDLR-deficient mice, a model for atherosclerosis. In this LDLR^–/– background the mutated mice showed a more atherogenic lipoprotein profile, which was associated with a decreased clearance of postprandial lipids because of a compromised endocytosis rate and reduced lipase activity. On an atherogenic diet LRP1 mutant mice revealed a 50% increased development of atherosclerosis. This aggravation was accompanied by an increase in smooth muscle cell (SMC) and collagen content and apoptotic cells in the lesions. The mutation showed, however, a limited impact on basal PDGFR-β expression and signaling and the antimigratory property of apoE on PDGF-BB–stimulated SMCs. Additionally, levels of LRP1 atherogenic ligands, like MMP2, t-PA, FVIII, and the inflammatory ligand TNF- showed to be significantly elevated.

Conclusion— These findings demonstrate that the NPxYxxL motif is essential for the atheroprotective role of LRP1. This motif is relevant for normal control of lipid metabolism and of atherogenic and inflammatory ligands, but has no pronounced effect on regulating PDGF-BB/PDGFR-β signaling in SMCs.

LRP1 knock-in mice carrying an inactivated NPxYxxL motif were crossed with LDLR-deficient mice. On this background knock-in mice had increased levels of postprandial lipids and atherogenic and inflammatory LRP1 ligands. These findings were associated with an aggravated atherosclerosis phenotype. No pronounced effect, however, was seen on LRP1-mediated PDGFR-β properties.

Key Words: atherosclerosis • growth factors • immune system • lipases • lipids