Atherosclerosis is a chronic inflammatory process where oxidative damage within the artery wall is implicated in the pathogenesis of the disease. Mononuclear phagocytes, an inflammatory cell capable of generating a variety of oxidizing species, are early components of arterial lesions. Their normal functions include host defense and surveillance through regulated generation of diffusible radical species, reactive oxygen or nitrogen species and HOCI (hypochlorous acid). However, under certain circumstances, an excess of these oxidizing species can overwhelm local antioxidant defenses and lead to oxidant stress and oxidative tissue injury, processes implicated in the pathogenesis of atherosclerosis. This proposal focuses on oxidation reactions catalyzed by myeloperoxidase (MPO) and the potential utility of protein oxidation products of distinct oxidation pathways to serve as non-invasive markers of oxidant stress in vivo. MPO is an abundant heme protein secreted from activated phagocytes and is present in human atherosclerotic lesions. MPO amplifies the oxidizing potential of H2O2 by using it as substrate to generate reactive halogen, aldehyde, nitrogen and diffusible radical species. We have recently shown that MPO is one pathway for protein and lipoprotein oxidation in vivo. Multiple distinct products of MPO are enriched in human atherosclerotic lesions and LDL recovered from human atheroma. However, the biological consequences of these MPO-catalyzed reactions are unknown. We will focus on two novel oxidation pathways recently identified for the enzyme: i) MPO can use H2O2 and nitrite (NO2-), the autoxidation product of NO, as co-substrates to form reactive nitrogen species; and ii) MPO generates a family of reactive aldehydes in high yield via HOCI-mediated oxidation of plasma amino acids. The overall goals of this proposal are to test the hypothesis that specific myeloperoxidase-generated oxidation products contribute to oxidative stress, cellular injury and convert LDL into an atherogenic form. We will determine whether monocytes employ MPO-generated reactive nitrogen species to mediate LDL protein nitration, lipid peroxidation, and the conversion of the lipoprotein into a form which promotes cholesterol accumulation in cells of the artery wall. We will establish whether structurally defined aldehydes derived from amino acid oxidation promote cell injury and oxidant stress, features implicated in the pathogenesis of inflammation and vascular disease. Finally, we will explore the role of urinary levels of amino acid oxidation products as non-invasive markers of oxidative stress in smokers and individuals with cardiovascular disease.
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