Oxidized low-density lipoprotein (Ox-LDL) has been suggested to play a major role in atherosclerosis. Despite the vast amount of pre-clinical evidence for its role in atherosclerosis, the negative outcomes of human clinical trials with antioxidants are of major concern. We address this paradox in this application and propose that antioxidants would adversely affect the conversion of lipid peroxide-derived aldehydes into carboxylic acids and inhibit the formation of products that could be anti-atherosclerotic. Based on preliminary data, we propose that the oxidation of lipid peroxidation-derived carboxaldehydes to dicarboxylic acids would be protective by shifting vulnerable plaques to more stable to plaque by promoting calcification. We propose three specific aims that would establish the formation of aldehyde and further oxidation products, the negative effects of antioxidants in inhibiting the formation of anti-atherosclerotic carboxylic acid products, and address the nature of anti-atherosclerotic effects of dicarboxylic acids. Overall, the study would provide a mechanism-based explanation for the failure of antioxidant clinical trials and will be unique and the first i proposing that a "natural" anti-inflammatory product (AZA) derived from "deleterious" lipid peroxidation products would act as an anti-atherosclerotic agent. The study overall will offer a biochemical explanation for the relationship between lipid peroxidation and calcification. The successful completion of the studies will not only help to understand the molecular mechanisms of atherosclerosis development but also would help to identify aldehyde oxidation as a molecular target for promotion and drug development.
This project will examine the potential benefits of the oxidation of lipid-peroxidation derived aldehydes into carboxylic acids in the atherosclerotic process. The project will also test the hypothesis that antioxidants will inhibit such oxidation, thereby exasperating the atherosclerotic process. Particular emphasis will be on the formation of dicarboxylic acids in promoting calcification, thus shifting vulnerable plaque formation to more stable plaques.