Oxidized LDL plays a central role in atherogenesis, but the mechanisms that damage LDL in vivo have yet to be identified. One possible agent is hypochlorous acid (HOCI), a potent microbicidal agent that is generated by phagocytes from hydrogen peroxide. We have shown that myeloperoxidase- generated HOCI converts cholesterol to chlorohydrins, which therefore may serve as markers for lipids oxidatively damaged by activated phagocytes. Myeloperoxidase can also directly oxidize the amino acid L-tyrosine. The proposed product, tyrosyl radical, is a long-lived, selectively reactive intermediate that crosslinks proteins by forming dityrosine, a stable product. Tyrosyl radical generated by myeloperoxidase initiates LDL lipid peroxidation, a key event in lipoprotein oxidation. We have also shown that myeloperoxidase and lipid-laden foam cells, the cellular hallmark of the early atherosclerotic lesion, co-localize in human atherosclerotic lesions. The demonstrated links between myeloperoxidase and lipoprotein oxidation strongly suggest that the enzyme may participate in the pathogenesis of vascular disease. The overall goal of this proposal is to test the hypothesis that myeloperoxidase is a catalyst for lipoprotein oxidation in vivo by searching for specific reaction products in human and rabbit atherosclerotic tissue.
The specific aims of the proposal are: A. To determine whether atherosclerotic lesions contain two products of myeloperoxidase action - dityrosine and cholesterol chlorohydrins. B. To explore the potential atherogenic properties of myeloperoxidase- modified LDL. C. To determine whether monocytes oxidize LDL cholesterol to chlorohydrins. D. To characterize the family of tyrosine oxidation products synthesized by myeloperoxidase. Our long-term goal is to understand the mechanisms that cause lipoprotein oxidation in the artery wall. This may permit the design of rational therapies to prevent the conversion of lipoproteins into atherogenic particles.
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