Immunization of apoE -/- mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis

Abstract

Aims Oxidation of low-density lipoprotein in the extracellular matrix of the arterial wall results in the formation of malondialdehyde (MDA) that modifies surrounding matrix proteins. This is associated with the activation of an immune response against modified extracellular matrix proteins present in atherosclerotic plaques. Clinical studies have revealed an inverse association between antibodies to MDA-modified fibronectin and risk for development of cardiovascular events. To determine the functional role of these immune responses in atherosclerosis, we performed studies in which apoE-deficient mice were immunized with MDA-modified fibronectin. Methods and results Immunization of apoE-deficient mice with MDA-modified fibronectin resulted in a 70 decrease in plaque area and a less inflammatory phenotype of remaining plaques. Immunization shifted a weak naturally occurring Th1 antibody response against MDAfibronectin into a Th2 antibody response. Cytokine expression and flow cytometry analyses of spleen cells from immunized mice showed an activation of regulatory T cells. Immunization with MDAfibronectin was also found to reduce plasma fibronectin levels. Conclusion Immunization with MDAfibronectin significantly reduces the development of atherosclerosis in apoE-deficient mice suggesting that the immune response observed in humans may have a protective effect. MDAfibronectin represents a possible novel target for immunomodulatory therapy in atherosclerosis. © The Author 2011.