Accelerated atherosclerosis in ApoE deficient lupus mouse models.
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.
Ma
Zhongjie
Z
Divisions of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Choudhury
Arpita
A
Kang
Sun-Ah
SA
Monestier
Marc
M
Cohen
Philip L
PL
Eisenberg
Robert A
RA
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology; D001011:Aorta / Q000276:immunology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001402:B-Lymphocytes / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006651:Histocytochemistry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000276:immunology
D000974:Antibodies, Antinuclear; D017152:Antibodies, Antiphospholipid; D000936:Antigen-Antibody Complex; D001057:Apolipoproteins E; D002784:Cholesterol