Oxidative modification of low density lipoprotein (LDL) is thought to be an important event during atherogenesis. The mechanism(s) by which lipoproteins are oxidized in vivo is largely unknown and a major-long term goal of this project. During the last several years we have explored the pro-oxidant activity of ceruloplasmin, a Cu-containing plasma protein, and have shown that it plays an important role in monocytic cell-mediated oxidative processes. Our evidence is that purified human ceruloplasmin induces LDL oxidation in vitro, that cultured monocytic cell-mediated oxidative processes. Our evidence is that purified human ceruloplasmin induces LDL oxidation in vitro, that cultured monocytic cells secrete ceruloplasmin is regulated at the mRNA and translational levels, and that immunohistochemical analysis shows that ceruloplasmin, in association with macrophages, is abundant in atherosclerotic lesions of human carotid endarterectomy specimens. These findings have led us to propose the following hypothesis: That lesion-derived cytokines stimulate macrophage production of ceruloplasmin, which as a Cu-containing, pro-oxidant molecule accelerates lipoprotein oxidation and atherosclerotic lesion formation. We will test this hypothesis by pursuing three specific aims. We will use biochemical and molecular approaches to determine the domains of ceruloplasmin involved in oxidant activity. We will investigate transcriptional and translational mechanisms that regulate ceruloplasmin synthesis by monocytic cells. Finally, we will determine the role of ceruloplasmin in vessel wall lipoprotein oxidation and atherosclerotic lesion formation in vivo. To accomplish this last aim, we will generate transgenic mice that over express ceruloplasmin and breed them with atherosclerosis-susceptible apo E-deficient mice. An understanding of the mechanisms underlying vessel wall oxidation processes is likely to have a major impact on the development of treatments that specifically reduce pathological oxidation while minimizing the effect of normal oxidative processes.
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