Deletion of Macrophage LDL Receptor–Related Protein Increases Atherogenesis in the Mouse

Abstract

Abstract-Macrophage low-density lipoprotein receptor-related protein (LRP) mediates internalization of remnant lipoproteins, and it is generally thought that blocking lipoprotein internalization will reduce foam cell formation and atherogenesis. Therefore, our study examined the function of macrophage LRP in atherogenesis. We generated transgenic mice that specifically lack macrophage LRP through Cre/lox recombination. Transplantation of macrophage LRP Ϫ/Ϫ bone marrow into lethally irradiated female LDLR Ϫ/Ϫ recipient mice resulted in a 40% increase in atherosclerosis. The difference in atherosclerosis was not caused by altered serum lipoprotein levels. Furthermore, deletion of macrophage LRP decreased uptake of 125 I-very-low-density lipoprotein compared with wild-type cells in vitro. The increase in atherosclerosis was accompanied by increases in monocyte chemoattractant protein type-1, tumor necrosis factor-␣, and proximal aorta macrophage cellularity. We also found that deletion of macrophage LRP increases matrix metalloproteinase-9. This increase in matrix metalloproteinase-9 was associated with a higher frequency of breaks in the elastic lamina. Contrary to what was found with other lipoprotein receptors, deletion of LRP increases atherogenesis in hypercholesterolemic mice. Our data support the hypothesis that macrophage LRP modulates atherogenesis through regulation of inflammatory responses. (Circ Res. 2007;100:670-677.) Key Words: low-density lipoprotein receptor-related protein Ⅲ atherosclerosis Ⅲ lipoproteins Ⅲ metalloproteinase Ⅲ macrophage F irst defined as a complex for removal of ␣ 2 -macroglobulin, 1,2 and then later identified as the lowdensity lipoprotein receptor (LDLR)-related protein (LRP), 3 LRP is a 600-kDa membrane receptor linked to numerous cellular functions and intracellular signaling events. 4 It has multiple extracellular ligands, including apolipoprotein E (apoE), lipoprotein lipase, plasma proteases (urokinase-type and tissue plasminogen activators), fibrinolytic factors (IXa and VIIIa), thrombospondin 1 and 2, and chaperone proteins receptor associated protein and heat shock protein-96 (reviewed elsewhere 5 ). The cytoplasmic tail of LRP binds to multiple intracellular adapter and scaffold proteins including disabled-1 and FE65. 6,7 LRP is present in numerous cell types, including macrophages and hepatocytes, and its systemic expression is essential for embryonic development. 8 A fundamental role for hepatic LRP in the clearance of plasma remnants has been demonstrated, as conditional hepatic LRP deletion results in increased plasma triglyceride and chylomicron levels, particularly in the absence of the LDLR. 9 Furthermore, decreased expression of hepatic LRP causes delayed chylomicron remnant clearance, supporting a protective effect of hepatic LRP on atherogenesis via reduced plasma lipoprotein burden. 10 Besides the effect on lipoprotein remnants, hepatic LRP may provide additional vascular protection by mediating the clearance of other proinflammatory ligands including matrix...

Molecular Basis for the Interaction of Low Density Lipoprotein Receptor-related Protein 1 (LRP1) with Integrin αMβ2

“…Given the importance of LRP1-␣ M ␤ 2 recognition in macrophage efflux and thus the resolution of acute inflammation, the information provided from this work may help us to better understand the role of LRP1 in inflammation. In this regard, conditional macrophage LRP1 knock-out mice exhibit proinflammatory phenotypes in animal models of atherosclerosis (43,44). Thus, this work may help us understand the role of LRP1 and ␣ M ␤ 2 in macrophage-mediated inflammatory response, its proper resolution, and the initiation of wound healing.…”

Aggregated Low-Density Lipoprotein Induces LRP1 Stabilization Through E3 Ubiquitin Ligase CHFR Downregulation in Human Vascular Smooth Muscle Cells

“…Deletion of macrophage LRP1 also increased atherogenesis in fat-fed LDLR-deficient mice, revealing a role for LRP1 in monocyte recruitment, regulation of inflammatory responses, and matrix metalloproteinases activity. 30,31 These effects can be, at least in part, attributed to the pivotal role of LRP1 in signal transduction. [32][33][34] In summary, results from the present study show that agLDL, one of the main LDL modifications in the arterial intima, prolongs the half life of LRP1 by preventing LRP1 ubiquitinylation through CHFR targeting.…”

Liver X Receptor–Mediated Induction of Cholesteryl Ester Transfer Protein Expression Is Selectively Impaired in Inflammatory Macrophages

“…20,21 Lipid entry and proinflammatory changes in macrophages are consecutive, but distinct processes and scavenger receptor-mediated lipid loading could be harmful only when associated with inflammation. [22][23][24] …”

“…20,21 Lipid entry and proinflammatory changes in macrophages are consecutive, but distinct processes and scavenger receptor-mediated lipid loading could be harmful only when associated with inflammation. [22][23][24] Interestingly, lipopolysaccharide (LPS)-mediated inflammation in CETPTg mice results in a profound decrease in hepatic CETP mRNA and plasma CETP concentration. 25 It remains unknown whether the regulation of CETP expression differs between macrophages and foam cells, and whether CETP gene is equally responsive to synthetic LXR agonists in early foam cells and in inflammatory cells that accumulate later in injured vascular wall.…”