XANTHINE OXIDASE AND VASCULAR DYSFUNCTION

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DESCRIPTION (Adapted from applicants' abstract) Reactive oxygen species induce changes in vascular function in conditions such as stroke, hypertension and atherosclerosis. The nature and complexity of lesion development in atherosclerosis suggest that the 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 concerning oxidant-induced damage in the vessel wall. It is hypothesized that impaired blood vessel function in hypercholesterolemic rabbits is due to the modification of nitric oxide (NO) by superoxide anion (O2-), leading to the production of the potent oxidant peroxynitrite (ONOO-). Reactive oxygen species are generated under normal physiological conditions, with native antioxidant scavengers minimizing oxidant-mediated injury. An imbalance in antioxidant defense mechanisms and changes in cellular metabolic processes then contributes to the development and progression of atherosclerotic disease. The studies outlined in this application are designed to provide new information describing the cellular mechanisms involved in these free radical reactions, namely that free radical injury in blood vessels of hypercholesterolemic rabbits is linked to the binding and concentration of xanthine oxidase (XO) at glycosaminoglycan (GAG) sites on the surface of endothelial cells and in the interstitial space. The hypothesis to be tested in this application is that GAG-bound XO is an important source of O2-, thus ONOO- formation, and contributes to the oxidative component of hypercholesterolemia. GAG 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 XO binding and incorporation, influencing changes in the vasculature and playing an important role in the pathological events associated with hyper-cholesterolemia. (End of Abstract)