COBRE Pilot Project for Vincent Venditto: Center of Research in Obesity and Cardiovascular Disease

Apolipoprotein A-I (ApoA-I) is the major protein of high-density lipoprotein (HDL). It is essential for HDL formation and the efflux of cholesterol from macrophage foam cells found in atherosclerotic plaques. Antibodies targeting this protein have been identified in obese patients and patients with autoimmune disorders. While the antibodies are correlated with an increased risk for major adverse cardiac events, the exact role of these antibodies in disease is unclear. Post-translational modifications of ApoA-I have been observed in patients with cardiovascular disease and these modifications have been shown to break tolerance in autoimmune disorders, suggesting a causative role in cardiovascular disease. However, these post- translational modifications do alter HDL function and may be protective by eliminating defective ApoA-I and HDL from circulation. The lack of appropriate animal models, however, prevents the elucidation of their role in disease. We hypothesize that an immunostimulatory formulation containing post-translationally modified peptide epitopes from ApoA-I will break tolerance in mice and generate a more efficient mouse model to study the role of antibodies in disease progression. Based on this hypothesis, we propose two aims to investigate the role of antibodies in cardiovascular disease. In AIM 1, we will measure the antibody titers directed toward ApoA-I in mice and monkeys with atherosclerotic plaques. We will correlate the antibody response to atherosclerotic plaque progression and dietary fat intake. In AIM 2 we will immunize mice using a multicomponent immunostimulatory formulation containing post-translationally modified peptide epitopes derived from ApoA-I and an adjuvant. This formulation is designed to break tolerance and induce a robust immune response toward self. The Aims proposed in this application will allow us to study the role of these autoantibodies in mice with the long term goal of developing therapeutics aimed at preventing and treating cardiovascular disease.