Accelerated atherosclerosis in ApoE deficient lupus mouse models

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.

Introduction

Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies against chromatin, Sm, DNA, and other nuclear antigens, as well as the deposition of Ig in various organs, including the kidneys and skin. These immunologic events are accompanied by the development of glomerulonephritis. However, the underlying mechanisms are not fully understood [1]. There are reports suggesting that deposition of immune complexes exacerbates the local inflammatory and autoimmune processes and thereby, accelerates atherosclerosis in SLE patients [2], [3]. In fact, SLE patients exhibit a higher incidence of atherosclerosis and are at significant risk for premature cardiovascular disease [4]. Elevated levels of anti-phospholipid antibodies, which are often found in people with lupus, have traditionally been linked to an increased risk of blood clotting and may increase the risk of clot formation at the plaque site [5]. Accumulating evidence supports an autoimmune mechanism as one of the prime pathogenic processes involved in the development of atherosclerosis [6]. More recent evidence suggests that these antibodies may also facilitate the uptake of oxidized low density lipoprotein into inflammatory cells in the vessel wall, which is a key step in the formation of atherosclerotic plaque [7], [8]. In order to determine whether the general inflammatory process of lupus enhances atherogenesis, we bred several different lupus susceptible mouse strains with the B6ApoE^−/− strain (apolipoprotein-E deficient) and tested the hypothesis that the combination of lupus and genetic mutations favored atherosclerosis in mice. We found that each model could modestly accelerate atherosclerosis compared to control B6ApoE^−/− mice. Our findings extend the work of others in the gld, lpr, and Sle1.2.3 models [9], [10], [11]. These mouse models may allow us further understanding of the interaction between SLE and atherosclerosis.