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Deficiency of receptor-associated protein attenuates angiotensin II-induced atherosclerosis in hypercholesterolemic mice without influencing abdominal aortic aneurysms - PubMed

Deficiency of receptor-associated protein attenuates angiotensin II-induced atherosclerosis in hypercholesterolemic mice without influencing abdominal aortic aneurysms

Shaoping Wang et al. Atherosclerosis. 2012 Feb.

Erratum in

  • Atherosclerosis. 2013 Oct;230(2):300

Abstract

Objective: Receptor-associated protein (RAP) was initially described as a regulator of low density lipoprotein receptor-related protein 1 (LRP1), but is now known to regulate many proteins. Since the direct effects of RAP on vascular pathologies have not been studied, this study determined whether RAP deficiency influenced angiotensin II (AngII)-induced atherosclerosis and abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice.

Methods and results: Male LDL receptor -/- mice that were either RAP +/+ or -/- were infused with AngII (500 ng/kg/min) for 4 weeks while consuming a saturated fat-enriched diet. RAP deficiency had no effects on body weight or AngII-induced increases of systolic blood pressure. Despite increased plasma cholesterol concentrations, RAP deficiency reduced atherosclerotic lesion size in aortic arches, while having no effect on AngII-induced AAAs. RAP deficiency profoundly reduced LRP1 protein abundance in macrophages, but did not change its abundance in aortic smooth muscle cells. Also, RAP deficiency had no effects on mRNA abundance of LRP1 or lipoprotein lipase in macrophages. To determine whether RAP deficiency in leukocytes influenced AngII-induced atherosclerosis, irradiated male LDL receptor -/- mice were repopulated with bone marrow-derived cells from either RAP +/+ or -/- male mice. The chimeric mice were infused with AngII (500 ng/kg/min) for 4 weeks while fed the saturated fat-enriched diet. RAP deficiency in bone marrow-derived cells did not influence either plasma cholesterol concentrations or atherosclerotic lesion size.

Conclusions: Whole body RAP deficiency attenuated atherosclerosis without influencing AAAs in hypercholesterolemic mice infused with AngII. The anti-atherogenic effect was not attributable to RAP deficiency in bone marrow-derived cells.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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Figures

Figure 1
Figure 1. RAP deficiency changed plasma lipoprotein distributions in hypercholesterolemic mice infused with AngII

(A) Lipoproteins were resolved by size exclusion chromatography of plasma from individual mice and cholesterol was measured using enzymatic kits in RAP +/+ (n = 10) or -/- (n = 12). Circles and error bars represent mean ± SEM. (B) Plasma concentrations of cholesterol in major lipoprotein fractions. Concentrations were calculated using plasma total cholesterol concentrations and non linear curve fitting of size exclusion profiles. Histobars represent means and bars represent SEM. * denotes P < 0.001 and # denotes P = 0.03, respectively.

Figure 2
Figure 2. RAP deficiency reduced atherosclerotic lesions in aortic arches in hypercholesterolemic mice infused with AngII

(A) Percent lesion areas and (B) Lesion areas in aortic arches were measured by an en face technique. * denotes P < 0.05 by a two-tailed Student's t test. Circles represent individual hypercholesterolemic mice that were either RAP +/+ (n = 17) or -/- (n = 14). Diamonds and error bars represent mean ± SEM.

Figure 3
Figure 3. RAP deficiency profoundly reduced the protein abundance of LRP1 in macrophages but not in SMCs

Western blots of RAP, LRP1, and β-actin were performed in (A) peritoneal macrophages and (B) SMCs isolated from aortic arches, and thoracic and abdominal aortas of RAP +/+ or -/- mice in an LDL receptor -/- background. Lanes 1 and 2 represent protein extracts from cultured SMCs of two independent experiments. In neither experiment did RAP deficiency affect LRP1 abundance.

Figure 4
Figure 4. RAP deficiency in bone marrow-derived cells had no effect on atherosclerosis in hypercholesterolemic mice infused with AngII

(A) RAP genotypes in bone marrow-derived cells of the recipient mice were verified by PCR. Amplicons of 75 bp and 130 bp represent wild-type allele and the disrupted allele of RAP, respectively. (B) Percent lesion areas in aortic arches were determined by the en face measurements. Circles represent individual recipient mice that were repopulated with bone marrow-derived cells from donor mice (RAP +/+, n = 22 and RAP -/-, n = 19). Diamonds and error bars represent mean ± SEM.

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References

    1. Strickland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, Argraves WS. Sequence identity between the a2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem. 1990;265:17401–17404. - PubMed
    1. Bu GJ, Geuze HJ, Strous GJ, Schwartz AL. 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein. EMBO J. 1995;14:2269–2280. - PMC - PubMed
    1. Lee D, Walsh JD, Mikhailenko I, Yu P, Migliorini M, Wu Y, Krueger S, Curtis JE, Harris B, Lockett S, Blacklow SC, Strickland DK, Wang YX. RAP uses a histidine switch to regulate its interaction with LRP in the ER and Golgi. Mol Cell. 2006;22:423–430. - PubMed
    1. Willnow TE, Armstrong SA, Hammer RE, Herz J. Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc Natl Acad Sci USA. 1995;92:4537–4541. - PMC - PubMed
    1. Willnow TE, Rohlmann A, Horton J, Otani H, Braun JR, Hammer RE, Herz J. RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors. EMBO J. 1996;15:2632–2639. - PMC - PubMed

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