ROLE OF MODIFIED LIPOPROTEINS AND THE IMMUNE SYSTEM IN ATHEROGENESIS

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The overall aim of this Unit is to investigate the role of modified lipoproteins and the immune response to these modifications in animal models of atherosclerosis. One of the most compelling lines of evidence supporting the oxidation hypothesis is the observation in 14 of 21 intervention studies that potent lipophilic antioxidants, such as probucol, inhibit the progression of atherosclerosis in animal models. However, in 5 studies, including two from our laboratory, antioxidants which provided less protection to LDL did not reduce atherogenesis. A major goal of this unit is to understand these exceptions. Specifically, we will test the hypothesis that for a given degree of oxidative stress a threshold level of protection for LDL must be achieved to reduce atherogenesis and that the threshold depends on the degrees of hypercholesterolemia. This hypothesis will be tested determining the antiatherogenic effect of a combination of natural and synthetic lipophilic antioxidants in LDL receptor-deficient (LDLR-/-) mice at different levels of diet-induced hypercholesterolemia. Conversely, the antiatherogenic effect of increasingly potent antioxidants, or combinations of antioxidants, will be tested at a constant level of plasma cholesterol. Knowledge that this hypothesis is correct would be important in designing clinical trials in man. The second aim of this Unit is to test the hypothesis that the oxidative modification of LDL and the generation of advanced glycation end products (AGE) by nonenzymatic glycation are mutually reinforcing, proatherogenic processes. This will be tested by intervention studies in euglycemic LDLR-/- rabbits and mice, which we have shown contain both AGE and OxLDL in atherosclerotic lesions. We will determine if antioxidants, or combinations of antioxidants and aminoguanidine, can inhibit both AGE and OxLDL formation. Finally, this Unit will explore the consequences of the observation that oxidized LDL is highly immunogenic. We will test the hypothesis that augmentation of immune responses to oxidized lipoproteins will in turn modulate lesion formation. We previously showed that hyperimmunization of WHHL rabbits with epitopes of OxLDL reduced atherosclerosis. We will now determine if a similar effect occurs in LDLR-/- and apoE-deficient mice immunized with epitopes of OxLDL, and will determine optimal immunogens and immunization regimens to inhibit atherosclerosis. We will also utilize hybrids of apaE-deficient or LDLR-/- mice and immune- deficient mice to determine the mechanisms by which immunization inhibits the atherogenic process. In summary, this Unit will investigate the ability of a variety of antioxidant and immunological interventions to reduce atherogenesis. The information gained should not only provide insight into basic atherogenic mechanisms, but may also provide useful information pointing to effective and novel therapeutic strategies.