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Vascular inflammation and atherosclerosis

Final Report Summary - ATHEROMOTO (Vascular inflammation and atherosclerosis)

Project context

Patients with aggressive inflammatory diseases, including autoimmune diseases, exhibit a higher incidence of atherosclerosis, suggesting that autoimmune processes may play a role in atherosclerosis progression. Despite awareness of this inflammatory nature of atherosclerosis, the causes of the inflammation and the exact nature of the putative antigens that elicit the immune reaction are not well characterised. One reason for this deficit is the lack of an appropriate animal model.

Project objectives

Our objectives were to create a mouse model combining autoimmunity and atherosclerosis and to investigate how hyperlipidemia affects autoimmune reactions and atherogenesis in this mouse model.

Project outcomes

We established a mouse model combining autoimmunity and hyperlipidemia by creating leukocyte deficiency in type IIB Fc Receptor (FcRIIB) in LDL receptor knockout background using bone marrow transplantation. We evaluated atherosclerosis progression in mice under two experimental settings; moderate and aggressive hyperlipidemia. Under aggressive Western diet conditions (plasma cholesterol levels around 800 mg/dl), and in the absence of FcRIIB, the mouse model was characterised by high levels of circulating immune complexes, immunoglobulin G and anti-nuclear antibodies, which are common in a typical autoimmune disease. In addition to impaired renal function and splenomegaly, the progression of atherosclerosis was more aggressive in these autoimmune mice. However, under moderate lipidemic conditions (plasma cholesterol levels around 400 mg/dl), levels of autoimmune markers were lower and the extent of atherosclerosis was similar with or without FgRIIB expression.

Using proteomic approaches, we discovered many molecular targets for these autoimmune reactions within the atherosclerotic plaques. We have concluded that autoimmunity accelerates atherogenesis, and hyperlipidemic conditions exasperate autoimmune responses leading to autoimmunity-driven atherosclerosis. Our results suggest that treatment of cardiovascular cases by lipid-lowering medication may slow down the inflammatory insult and protect against the progression of cardiovascular disease.