Immunization of LDL receptor-deficient mice with β₂-glycoprotein 1 or human serum albumin induces a more inflammatory phenotype in atherosclerotic plaques

Summary

Antiphospholipid antibodies are a risk factor for venous and arterial thrombosis and may contribute to the development of atherosclerosis. The aim of this study was to investigate whether antibodies to human β₂-glycoprotein 1 (β₂ GP1), as a model of antiphospholipid antibodies, modify the phenotype of atherosclerotic lesions. LDL receptor-deficient mice were immunized with human β₂ GP1, human serum albumin (HSA), or not immunized, and fed a high-cholesterol diet for 14 weeks. Some mice also received pravastatin. Immunization with human β₂ GP1 or HSA resulted in formation of autoantibodies recognizing murine β₂ GP1 or murine albumin, respectively. We quantified atherosclerotic lesion development and mRNA levels of inflammationassociated proteins in the thoraco-abdominal aorta as well as lesion development, cellular composition and collagen content in the aortic roots. Immunization with β₂ GP1 or HSA had no effect on lesion size, but modified the expression in plaque areas of several inflammation-associated proteins. Expression of matrix metalloproteinase-9, tissue factor, interferon-gamma and CD25 was highest in the thoraco-abdominal aorta of β₂ GP1-immunized mice, lowest in non-immunized mice and intermediate in HSA-immunized animals. Immunization with β₂ GP1, but not HSA, resulted in a lower smooth muscle cell and collagen content of lesions in aortic roots. Statin treatment partially reversed the effects of β₂ GP1 immunization. We conclude that immunization with β₂ GP1, and to a lesser extent with HSA, leads to modifications in the cellular and protein composition of atherosclerotic plaques, which are associated with a more inflammatory phenotype. Statin treatment partially prevents these changes.

Keywords

Antiphospholipid antibodies - atherosclerosis - β₂-glycoprotein 1 - immunization - statins

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