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

Department of Medicine, Vanderbilt University, Нашвилл, Michigan, United States
Circulation Research (Impact Factor: 11.02). 04/2007; 100(5):670-7. DOI: 10.1161/01.RES.0000260204.40510.aa
Source: PubMed


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(-/-) bone marrow into lethally irradiated female LDLR(-/-) 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-alpha, 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.

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    • "One key receptor in the modulation of MMP-9 and MMP-2 activity is LRP1 [6] [7]. It has been demonstrated that LRP1 deficiency causes MMP-9 overexpression in mouse macrophages [8], inhibition of cell migration in rat Schwan cells [9], and, by downregulation of MMP-2 expression, decreased angiotensin II-induced migration of rat aortic smooth muscle cells [10]. "
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    ABSTRACT: LRP1-pPyk2 axis is essential for the upregulatory effect of hypoxia on MMP-9 activation and human VSMC (hVSMC) migration. Currently, there are not efficient models for the translational study of atherosclerosis. The morphological and physiological features of atherosclerosis are different between human and animal models, particularly in mouse models. Therefore, the aim of current investigation was to compare the effect of hypoxia on LRP1-Pyk2-MMP-9 axis in human and mouse vascular smooth muscle cells (mVSMC) and its consequences on VSMC migration. We demonstrated that hypoxic modulation of LRP1-pPyk2-MMP-9 axis is opposite between hVSMC and mVSMC. The modulation of LRP1/pPyk2 levels by hypoxia is positive in hVSMC but negative in mVSMC. We showed that the inverse effect of LRP1/pPyk2 axis is associated with a differential effect of hypoxia on MMP-9 expression and activation. Hypoxia-induced MMP-9 activation was concomitant with an increased hVSMC migratory capacity. Surprisingly, mVSMC migrate under hypoxic conditions despite the downregulatory effect of hypoxia on MMP-9 expression or activation. Our results highlight the crucial role of LRP1-pPyk2-MMP-9 axis in vascular cell migration. In addition, we propose that the extrapolation of results from animal models to humans is not suitable for this specific mechanism in hypoxia-related vascular conditions.
    Full-text · Article · May 2015
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    • "In order to test MΦ LRP function in iNKT cell activation, we used mice harboring a MΦ knockout of LRP [37]. In this mouse model, LRPflox/flox mice were crossed with LyzM-Cre mice, which have cre recombinase under the control of the lysozyme M promoter. "
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    ABSTRACT: Expression of molecules involved in lipid homeostasis such as the low density lipoprotein receptor (LDLr) on antigen presenting cells (APCs) has been shown to enhance invariant natural killer T (iNKT) cell function. However, the contribution to iNKT cell activation by other lipoprotein receptors with shared structural and ligand binding properties to the LDLr has not been described. In this study, we investigated whether a structurally related receptor to the LDLr, known as LDL receptor-related protein (LRP), plays a role in iNKT cell activation. We found that, unlike the LDLr which is highly expressed on all immune cells, the LRP was preferentially expressed at high levels on F4/80+ macrophages (MΦ). We also show that CD169+ MΦs, known to present antigen to iNKT cells, exhibited increased expression of LRP compared to CD169- MΦs. To test the contribution of MΦ LRP to iNKT cell activation we used a mouse model of MΦ LRP conditional knockout (LRP-cKO). LRP-cKO MΦs pulsed with glycolipid alpha-galactosylceramide (αGC) elicited normal IL-2 secretion by iNKT hybridoma and in vivo challenge of LRP-cKO mice led to normal IFN-γ, but blunted IL-4 response in both serum and intracellular expression by iNKT cells. Flow cytometric analyses show similar levels of MHC class-I like molecule CD1d on LRP-cKO MΦs and normal glycolipid uptake. Survey of the iNKT cell compartment in LRP-cKO mice revealed intact numbers and percentages and no homeostatic disruption as evidenced by the absence of programmed death-1 and Ly-49 surface receptors. Mixed bone marrow chimeras showed that the inability iNKT cells to make IL-4 is cell extrinsic and can be rescued in the presence of wild type APCs. Collectively, these data demonstrate that, although MΦ LRP may not be necessary for IFN-γ responses, it can contribute to iNKT cell activation by enhancing early IL-4 secretion.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Loss of vascular LRP1 has been shown to result in greater VSMC proliferation, deficient contractile protein expression, impairment of vascular contractility, and promotion of denudation-induced neointimal hyperplasia. 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 MMP activity [17] [18]. These effects can be, at least in part, attributed to the pivotal role of LRP1 in signal transduction [19e21]. "
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    ABSTRACT: Introduction and objectivesLRP1 gene overexpression in atherosclerotic plaque is associated with increased lipid uptake through the vascular wall. The aim of the study was to analyze whether LRP1 modulates the genetic risk of developing premature cardiovascular disease in familial hypercholesterolemia, using single nucleotide polymorphism association analysis.Methods Ten polymorphisms of the LRP1 gene (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164, and rs35282763) were genotyped in 339 patients (77 with premature cardiovascular disease and 262 without) in the SAFEHEART study.ResultsThe c.677C>T (rs1799986) polymorphism showed a significant association with premature cardiovascular disease after adjusting by sex, age, body mass index, and the effect of the low-density lipoprotein receptor mutation in the dominant model (CT+TT vs CC: odds ratio=1.94; 95% confidence interval, 1.08-3.48; P=.029). Similar results were observed after increasing the sample to 648 subjects (133 with premature cardiovascular disease vs 515 without [odds ratio=1.83; 95% confidence interval, 1.16-2.88; P=.011]).Conclusions The c.677C>T polymorphism is associated with increased rates of premature cardiovascular disease in familial hypercholesterolemia. Although we were unable to show that this polymorphism was involved in the alteration of normal mRNA splicing patterns, the possibility that it is in strong linkage disequilibrium with another functional polymorphism cannot be ruled out and would explain the cause-effect relationship with cardiovascular disease risk in this population. Further studies are needed to replicate the results and to localize the putative genetic variants associated with this polymorphism.Full English text available
    Full-text · Article · Sep 2012 · Revista Espa de Cardiologia
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