Regulation of prostaglandin H2 synthase by nitrogen oxides

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In arteries, prostacyclin (PGI2) and nitric oxide (NO.) are second messengers that regulate processes such as vasodilation, cholesterol trafficking and smooth muscle cell proliferation. During atherogenesis, NO. production is elevated, but vasorelaxation is impaired. Excess NO. produced during this disease may be scavenged by superoxide, leading to peroxynitrite (ONOO-) formation, which may cause pathophysiological effects, including tyrosine nitration of proteins. Since both NO. and POGI2 perform similar functions and are stimulated by the same inflammatory cytokines, we and others have hypothesized that the NO. and arachidonic acid metabolism by direct interaction with the enzyme that initiates this process, prostaglandin H2 synthase (PGHS; also known as cyclooxygenase). While one form of Nox, viz. ONOO-, activates PGHS-1, another form, NO., inhibits PGHS-1 activity. The mechanisms of Nox modulation of PGHS activity remain undefined. We designed experiments to address these mechanisms of action in Specific Aim 1. Because NOX may also modulate arachidonic acid metabolism by activating signaling molecules that lead to arachidonic acid release in vascular cells, studies are designed to characterize the effects of Nox on signaling cascades leading to arachidonic acid mobi8lization in Specific Aim 2. Finally, although ONOO- initially activates PGHS, it also contributes to biological damage. The vasculature may initially employ PGHS to detoxify ONOO-; and in this process, synthesize eicosanoids that are beneficial to restoring vascular hemostasis. As the disease progresses, however, oxidation of biological targets occur, such as tyrosine nitration of proteins, causing loss of function. In Specific Aim 3, we proposes to characterize the extent of PGHS nitration in atheromatous plaques. These experiments are a natural extension of our previous work, and we will continue to capitalize on the talents of our other PPG investigators (Drs. Gross, Hempstead, Silverstein) to advance these goals.