The focus of this proposed research is to define mechanisms underlying the production and reactions of .NO and peroxynitrite (ONOO-) with lipids and lipid radicals (LO. And LOO.) formed during membrane and lipoprotein oxidation. Special attention will also be paid to the direct reactions and indirect protective effects that .NO exerts towards the key membrane and lipoprotein antioxidants, alpha-tocopherol and ascorbate in chemical and cell studies. To understand the conditions and reactions underlying the dual protective and toxic aspects of the free radical reactivities of .NO, four experimental aims will be pursued to test the hypothesis that .NO can regulate oxidant/inflammatory injury in the vascular compartment by accelerating oxidative events via peroxynitrite (ONOO-) formation or alternatively, by chemically terminating free radical species. This will lead to modulation of inflammatory events and yield nitrogen-containing products having unique reactivities. Specifically, the principal investigator will 1) examine the reactions of .NO, reactive oxygen species and ONOO- with free and esterified unsaturated fatty acids (linoleic and arachidonic acids), 2) characterize the principal .NO/ONOO- derivatives of oxidized lipids (e.g. LONO/LNO2 and LOONO/LONO2 species) formed in oxidizing lipid systems and define their biochemical properties, 3) define the impact of .NO on integrated membrane and lipoprotein antioxidant defenses, focusing on the direct and indirect interactions of .NO with alpha-tocopherol, -tocopherol and ascorbic acid and 4) examine the actions of .NO in a cell model of oxidative and inflammatory injury. Successful accomplishment of the proposed aims will develop and solidify the concept that reactions between oxidized biomolecules and .NO a) mitigate pathologic events and b) yield reactive nitrogen-containing products. In particular, the principal investigator will reveal mechanisms and conditions underlying the dual capacity of .NO to mediate both tissue protection and injury, especially within the context of .NO serving as both a prooxidant and antioxidant species. The proposed research also provides a framework for the characterization of newly described lipid species that are formed during vascular inflammatory events.
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