There is great interest in the role of nitric oxide (NO) in biology because it can be a signaling molecule, a toxin, a pro-oxidant and a potential antioxidant. It is involved in: signaling in vasodilation and neurotransmission, as a toxin in the destruction of pathogens, and as a potential chain-breaking antioxidant in lipids and lipid structures. NO can serve as a chain-terminating antioxidant during lipid peroxidation. We will test the hypothesis that nitric oxide can be an important chain-breaking antioxidant in cellular membranes; nitric oxide protects cell membranes from the damage that can be rendered by free radical-mediated lipid peroxidation. Vitamin E has traditionally been thought to be the principal, small-molecule, chain-breaking antioxidant in biological lipid structures. However, this paradigm was established in experimental systems that did not include nitric oxide. Thus, we will also test the hypothesis that nitric oxide can be as, or even more, important than vitamin E. To examine this hypothesis we will: 1. Determine the concentration of nitric oxide that is required to slow or stop the free radical-mediated chain reactions of lipid peroxidation in cells and relate this to the flux of oxygen-centered radicals in cellular lipid structures; 2. Determine the relative importance of vitamin E and nitric oxide as chain-breaking antioxidants in the lipid structures of cells; 3. Determine if nitric oxide, when serving as a chain-breaking antioxidant, is able to protect cells from lethal damage induced by free radical mediated lipid peroxidation. The inhibition of lipid peroxidation in cells will be analyzed on a kinetic basis so quantitative comparisons of the ability of nitric oxide and vitamin E to serve as chain-breaking antioxidants can be accomplished. This project will provide concrete kinetic information to help elucidate the role of nitric oxide in disease states that have associated lipid peroxidation.
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