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

Hu, Lu; Boesten, Lianne S.M.; May, Petra; Herz, Joachim; Bovenschen, Niels; Huisman, Menno V.; Berbée, Jimmy F.P.; Havekes, Louis M.; Vlijmen, Bart J.M. van; Tamsma, J. T.

doi:10.1161/01.atv.0000249641.96896.e6

Cited by 59 publications

(61 citation statements)

References 37 publications

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“…Such ligands will not include cholesterol or triglycerides, because their levels have been found to be normal in macLRP1 Ϫ mice. 26 In the current study, we have focused on the possibility that macLRP1 modulates clearance of VWF. Indeed, we did see a longer survival of both FVIII and VWF in the absence of macLRP1 (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Previous analysis of these mice has shown that more than 90% of these macrophages are deficient in LRP1, which has been confirmed for our colony. 26,30 Housing and experiments were done as recommended by French regulations and the experimental guidelines of the European Community. Animal experiments were approved by the Animal Care and Use Committee of Inserm (license B-94-043-13).…”

Section: Micementioning

confidence: 99%

“…[26][27][28][29][30] LRP1 flox/flox /LysM-Cre ϩ mice are characterized by the genetic inactivation of the LRP1 gene in cells expressing Lysozyme M, which include macrophages. Previous analysis of these mice has shown that more than 90% of these macrophages are deficient in LRP1, which has been confirmed for our colony.…”

Section: Micementioning

confidence: 99%

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Macrophage LRP1 contributes to the clearance of von Willebrand factor

Rastegarlari

Pegon

Casari

et al. 2012

Blood

103

130

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The relationship between low-density lipoprotein receptor-related protein-1 (LRP1) and von Willebrand factor (VWF) has remained elusive for years. Indeed, despite a reported absence of interaction between both proteins, liver-specific deletion of LRP1 results in increased VWF levels. To investigate this discrepancy, we used mice with a macrophagespecific deficiency of LRP1 (macLRP1 ؊ ) because we previously found that macrophages dominate VWF clearance. Basal VWF levels were increased in macLRP1 ؊ mice compared with control mice (1.6 ؎ 0.4 vs 1.0 ؎ 0.4 U/mL). Clearance experiments revealed that half-life of human VWF was significantly increased in macLRP1 ؊ mice. Ubiquitous blocking of LRP1 or additional lipoprotein receptors by overexpressing receptor-associated protein in macLRP1 ؊ mice did not result in further rise of VWF levels (0.1 ؎ 0.2 U/mL), in contrast to macLRP1 ؉ mice (rise in VWF, 0.8 ؎ 0.4 U/mL). This points to macLRP1 being the only lipoprotein receptor regulating VWF levels. When testing the mechanism(s) involved, we observed that VWFcoated beads adhered efficiently to LRP1 but only when exposed to shear forces exceeding 2.5 dyne/cm 2 , implying the existence of shear stress-dependent interactions. Furthermore, a mechanism involving ␤2-integrins that binds both VWF and LRP1 also is implicated because inhibition of ␤2-integrins led to increased VWF levels in control (rise, 0.19 ؎ 0.16 U/mL) but not in macLRP1 ؊ mice (0.08 ؎ 0.15 U/mL). (Blood. 2012; 119(9):2126-2134) Introductionvon Willebrand factor (VWF) is a hemostatic protein, the physiologic relevance of which is illustrated by the severe bleeding tendency associated with its functional deficiency. The contribution of VWF to hemostasis is 2-fold: (1) VWF is essential for the recruitment of platelets to the damaged vessel wall, particularly under conditions of arterial shear; and (2) VWF functions as a carrier protein for factor VIII (FVIII), a protein cofactor critical to the coagulation system.Whereas biosynthesis and secretion of VWF have been subject of study for more than 35 years, it is only in the last decade that clearance mechanisms of VWF have gained attention. 1,2 This has led to the discovery that increased clearance of VWF may explain part of the reduced VWF levels in von Willebrand disease (VWD). [3][4][5][6] This seems to be most prominent in case of VWDtype 1, although VWD-type 2 variants also are associated with reduced survival of the mutated VWF molecules. 2,7,8 The increased attention is further related to the development of novel therapeutic FVIII concentrates that are used in the treatment of hemophilia A. Given that FVIII circulates in a tight complex with VWF, it is already known that VWF is a major determinant of FVIII clearance. Indeed, the half-life of FVIII is considerably reduced in patients lacking VWF antigen or in those in which VWF is unable to bind FVIII correctly (VWD-type 2N). 9,10 Moreover, preinfusion VWF levels are positively correlated with FVIII half-life. 11,12 To this end, we have recently demonstrate...

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Section: Discussionmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

See 1 more Smart Citation

Macrophage LRP1 contributes to the clearance of von Willebrand factor

Rastegarlari

Pegon

Casari

et al. 2012

Blood

103

130

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“…27 Lesion area and composition with regard to adherent monocytes, macrophages, collagen, smooth muscle cells (SMCs), and T cells were determined. 29 …”

Section: Atherosclerotic Lesion Analysismentioning

confidence: 99%

Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E–Knockout Mice

et al. 2007

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Background-Lipopolysaccharide (LPS), which is released from Gram-negative bacteria on multiplication or lysis, aggravates atherosclerosis in humans and rodents by inducing inflammation via toll-like receptors. Because apolipoprotein C-I (apoCI) enhances the LPS-induced inflammatory response in macrophages in vitro and in mice, we investigated the effect of endogenous apoCI expression on LPS-induced atherosclerosis in mice. Methods and Results-Twelve-week-old apoe Ϫ/Ϫ apoc1 Ϫ/Ϫ and apoe Ϫ/Ϫ apoc1 ϩ/ϩ mice received weekly intraperitoneal injections of LPS (50 g) or vehicle for a period of 10 weeks, and atherosclerosis development was assessed in the aortic root. LPS administration did not affect atherosclerotic lesion area in apoe Ϫ/Ϫ apoc1 Ϫ/Ϫ mice but increased it in apoe Ϫ/Ϫ apoc1 ϩ/ϩ mice. In fact, apoCI expression increased the LPS-induced atherosclerotic lesion area by 60% (PϽ0.05), concomitant with an increase in LPS-induced plasma levels of fibrinogen and E-selectin. This indicated that apoCI increased the LPS-induced inflammatory state, both systemically (ie, fibrinogen) and at the level of the vessel wall (ie, E-selectin). In addition, both macrophage-derived apoCI and HDL-associated apoCI increased the LPS-induced tumor necrosis factor-␣ response by macrophages in vitro. Conclusions-We conclude that apoCI is crucially involved in LPS-induced atherosclerosis in apoe Ϫ/Ϫ mice, which mainly relates to an increased inflammatory response toward LPS. We anticipate that apoCI plasma levels contribute to accelerated atherosclerosis development in individuals who have chronic infection.

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“…Various types of lesions were discerned: no lesions, mild lesions (types 1-3), and severe lesions (types 4 -5). Immunohistochemistry for determination of lesion composition was performed as described previously (10). Rat anti-mouse antibody MAC3 (1:1,000; BD Pharmingen, Breda, The Netherlands) was used to quantify macrophage area.…”

Section: Methodsmentioning

confidence: 99%

Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development

Kooijman

Meurs

Beek

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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The brain plays a prominent role in the regulation of inflammation. Immune cells are under control of the so-called cholinergic anti-inflammatory reflex, mainly acting via autonomic innervation of the spleen. Activation of this reflex inhibits the secretion of proinflammatory cytokines and may reduce the development of atherosclerosis. Therefore, the aim of this study was to evaluate the effects of selective parasympathetic (Px) and sympathetic (Sx) denervation of the spleen on inflammatory status and atherosclerotic lesion development. Female APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism and atherosclerosis, were fed a cholesterol-containing Western-type diet for 4 wk after which they were subdivided into three groups receiving either splenic Px, splenic Sx, or sham surgery. The mice were subsequently challenged with the same diet for an additional 15 wk. Selective Px increased leukocyte counts (i.e., dendritic cells, B cells, and T cells) in the spleen and increased gene expression of proinflammatory cytokines in the liver and peritoneal leukocytes compared with Sx and sham surgery. Both Px and Sx increased circulating proinflammatory cytokines IL-1β and IL-6. However, the increased proinflammatory status in denervated mice did not affect atherosclerotic lesion size or lesion composition. Conclusion: Predominantly selective Px of the spleen enhances the inflammatory status, which, however, does not aggravate diet-induced atherosclerotic lesion development.

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

Cited by 59 publications

References 37 publications

Macrophage LRP1 contributes to the clearance of von Willebrand factor

Macrophage LRP1 contributes to the clearance of von Willebrand factor

Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E–Knockout Mice

Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development

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