Reactive oxygen species induced changes in vascular function and conditions such as stroke, hypertension, and atherosclerosis. The nature and complexity of lesion development in atherosclerosis suggests that this disease may have several etiologies. The generation of free radicals is associated with alterations in both vascular reactivity and lipoprotein metabolism. The studies proposed in this application are designed to provide new information about oxidant-induced damage in the vessel wall. The hypothesis to be tested is that impaired blood vessel function in hypercholesterolemic rabbits is a consequence of the interaction between nitric oxide and superoxide anion radical, leading to the production of the potent oxidant peroxynitrite. Reactive oxygen species are generated under normal physiologic conditions, with native antioxidant scavenger pathways developed to minimize oxidant-mediated injury. In imbalance in antioxidant defense mechanisms and changes in cellular metabolic processes then contribute to the development and progression of atherosclerotic disease. The studies outlined in this proposal are designed to provide new information describing the cellular mechanisms involved in these free radical reactions, viz., that free radical injury in blood vessels of hypercholesterolemic rabbits is linked to the binding and concentration of xanthine oxidase at glycosaminoglycan sites on the surface of endothelial cells and in the interstitium of the vasculature. The hypothesis to be tested in this proposal is that glycosaminoglycan- bound xanthine oxidase is an important source of superoxide anion radical and, thus, peroxynitrite, and contributes to the oxidative component of hypercholesterolemia. Glycosaminoglycan function or expression may be altered by hyperlipidemia, thereby facilitating incorporation of lipoproteins in the vessel wall as well as serving as a site for xanthine oxidase binding and incorporation. These changes in molecular interactions can influence changes in vascular function and play an important role in the pathologic events associated with hypercholesterolemia.
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