NITRIC OXIDE INHIBITION OF APO-B-MEDIATED LDL OXIDATION

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The experimental goals described in this new FIRCA application address fundamental mechanisms underlying the principal source of morbidity and mortality in Westernized countries, atherosclerosis. They also serve as the foundation for further expanding the mutually beneficial collaborative research and training activities in free radical biology and medicine shared by investigators at the University of Alabama at Birmingham School of Medicine and the Facultad de Medicina of the Universidad de la Repdblica in Montevideo, Uruguay. Specifically, the theme of the parent grant, that -NO mediates antioxidant actions in membrane lipids and lipoproteins, will be expanded in a new and important direction by addressing the novel concept that -NO can exert these effects by interacting with protein- based radicals. It is hypothesized that -NO plays a critical role in modulating LDL oxidation by: a) a facile diffusion capacity into both the surface and the core of the LDL particle, thus representing the major antioxidant species in the lipophilic core of LDL, and b) diffusion- controlled reactions with apoB-100-centered amino acid radicals, thus inhibiting both lipid and protein oxidation reactions. In addition, we postulate that chemical interactions of the vasodilator -NO with amino acid components of plasma LDL apoB-100 serve to concentrate and later release -NO, thus mitigating the otherwise pro-atherogenic effects of oxidized LDL. To address these concepts, two key experimental aims will be pursued. We will 1) Measure rates of -NO diffusion and partitioning into human plasma LDL and 2) Identify -NO adducts with apo B-100 amino acid radicals and define the antioxidant and signaling roles of these novel species. These proposed investigations will provide a strong foundation for understanding mechanisms underlying the profound impact that -NO has on the initiation, propagation and resolution of both LDL oxidation and consequent atherogenic events. Thus, the research plan will explore novel chemical interactions of -NO with lipoproteins, yielding new insight into -NO-dependent anti- atherogenic processes.