Accelerated atherosclerosis in ApoE deficient lupus mouse models - PubMed (original) (raw)

Accelerated atherosclerosis in ApoE deficient lupus mouse models

Zhongjie Ma et al. Clin Immunol. 2008 May.

Abstract

The accelerated development of atherosclerosis with increased risk of cardiovascular disease in systemic lupus erythematosus (SLE) patients is not well understood. An appropriate mouse model would greatly help to understand the mechanisms of this association. We have therefore combined the ApoE(-/-) model of atherosclerosis with three different murine models of SLE. We found that induction of cGVH in B6.ApoE(-/-) mice, breeding a Fas null gene onto the B6.ApoE(-/-) mice, and breeding the ApoE(-/-) defect onto MRL/lpr mice all caused a modest increase of atherosclerosis at 24 weeks of age compared to B6.ApoE(-/-) controls. B cells in B6.ApoE(-/-) mice had certain phenotypic differences compared to congenic C57BL/6 mice, as indicated by high expression of MHC II, Fas, CD86, and by increased number of cells bearing marginal zone phenotype. Furthermore, B6ApoE(-/-) mice had significant titers of anti-oxLDL and anti-cardiolipin autoantibodies compared to their B6 counterparts. Our studies also indicate that, following induction of cGVH, marginal zone B cells in B6.ApoE(-/-) are depleted, and there is considerable increase in anti-oxLDL and anti-cardiolipin abs along with secretion of lupus-specific autoantibodies, such as anti-dsDNA and anti-chromatin abs. Histological sections showed that cGVH and/or Fas deficiency could exacerbate atherosclerosis. The production of anti-oxLDL and anti-cardiolipin in ApoE(-/-) mice was also increased. These observations define a connection between induction of lupus-like symptoms and development of severe atherosclerosis in ApoE deficient lupus mouse models.

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Figures

Figure 1

Figure 1. Total plasma cholesterol in SLE mice

Plasma total cholesterol levels were significantly increased in all ApoEKO mice compared to B6 control. *, p<0.05, comparing lupus-prone-ApoEKO and corresponding controls. #, p<0.05, comparing MRL/lpr and B6 control. +, p<0.05, comparing B6/lpr.ApoE-/- and B6.ApoE-/-; and comparing MRL/lpr.ApoE-/- and B6.ApoE-/-, respectively. For each strain, data are pooled from 5 females and 4 males.

Figure 2

Figure 2. Accelerated atherosclerosis in lupus ApoE deficient mouse

The aortic tree was stained with Sudan IV for en face analysis (A). Data pooled from 7-9 mice are shown in B. Aorta root lesions were stained in cross section with Oil red O (C). Lesion quantification for 9 mice (5 females and 4 males) is shown in D. *, p<0.05, comparing lupus-prone-ApoEKO and B6.ApoEKO. The arrows indicate atherosclerotic plaques.

Figure 3

Figure 3. Autoantibodies in ApoE-/- SLE mice

ELISA results are shown in for total IgG (A); anti-dsDNA (B); and anti-chromatin (C). Serum total IgG, anti-dsDNA, and anti-chromatin were increased both in lupus-prone mice and in lupus-prone-ApoE deficient mouse. However, no significant differences were found between SLE mice for each model and its comparable ApoE-/- strain. *, p<0.05, comparing lupus-prone, lupus-prone-ApoEKO with B6 control. Data are pooled from 5 females and 4 males in each strain.

Figure 4

Figure 4. Anti-phospholipid antibodies in SLE mice

Anti-oxLDL IgG and IgM are shown in (A). Anti-cardiolipin IgG and IgM are shown in (B). *, p<0.05, comparing lupus-prone-ApoEKO and corresponding lupus-prone controls. #, p<0.05, comparing B6.ApoEKO, lupus-prone-ApoEKO with B6 control. Data are pooled from 5 females and 4 males in each strain.

Figure 5

Figure 5. B cell activation in B6._ApoE_-/- mice

Splenic lymphocytes were analyzed at thirteen weeks post induction of cGVH. Cells were gated by size and CD19. (A) histograms from one representative mouse in each group; (B) means and SD. *, p<0.05, comparing B6.ApoEKO (N = 5 females) and B6 control (N = 3 females). MFI=Mean Fluorescence Intensity.

Figure 6

Figure 6. B cell subsets in B6._ApoE_-/- mice

Splenic lymphocytes were analyzed at thirteen weeks post induction of cGVH. Cells were gated by size and CD19, and stained for CD21 and CD23. Marginal zone (MZ), follicular (FO) and newly formed (NF) subsets were gated as shown in A. (A) scatter plots of data from one representative mouse in each group; (B) means and SD for all mice examined. *, p<0.05, comparing cGVH and control recipients. #, p<0.05, comparing B6-GVH (N = 5 females), B6.ApoE-GVH (N = 5 females), with corresponding controls (N = 3 females).

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