Studies from the applicant's laboratory and those of others suggest that interactions between nitric oxide and the superoxide anion are critically important in determining nitric oxide's effect in several pathologic processes. During the past funding period, it was shown that increased production of superoxide contributes to alterations of endothelium-dependent vascular relaxation in hypercholesterolemia and in the setting of nitrate tolerance. In the latter situation, this has been found to be due to activation of a specific membrane-bound oxidase which seems to be regulated by angiotensin II. More recently, the applicant has demonstrated that hypertension caused by infusions or relatively low concentrations of angiotensin II in the rat is associated with activation of a similar oxidase, a doubling of vascular superoxide production, and in impairment of endothelium-dependent vascular relaxation. The studies outlined in this application are aimed at determining whether this phenomenon is due to a direct effect of angiotensin II or if it is mediated by a mechanical influence of pressure. The role of increased vascular superoxide production in angiotensin II-induced hypertension will be investigated by treating the animals with either liposomal-encapsulated superoxide dismutase or heparin-binding superoxide dismutase. Because heparin-binding superoxide dismutase remains extracellular, studies with this agent should help identify the site at which superoxide interacts with nitric oxide. Studies will be performed to determine if angiotensin II-induced hypertension decreases vascular antioxidant defense mechanisms, which could increase steady state superoxide release in the face of unaltered superoxide generation. The role of a recently cloned vascular smooth muscle p22phox protein which has similarities to the small subunit of the membrane b558 neutrophil oxidase system will also be examined. Preliminary data shows that p22phox is induced by angiotensin II-infusion in rats and that overexpression of the enzyme in stably transfected vascular smooth muscle cells increases NADH-driven superoxide production. These studies will involve expression of p22phox in a baculovirus/sf-9 system as a means of purifying other subunits of the enzyme. Finally, the role of binding of other subunits to the cytoplasmic domain of p22phox in activation of the enzyme will be determined. Overall, these studies should provide new insights into mechanisms regulating vascular superoxide production and reactivity.
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