Regulation of prostaglandin H2 synthase by nitrogen oxides

在动脉中，前列环素（PGI2）和一氧化氮（NO）是调节血管舒张、胆固醇运输和平滑肌细胞增殖等过程的第二信使。在动脉粥样硬化过程中，NO。生产增加，但血管松弛受损。没有过剩。在这种疾病中产生的超氧化物可能被清除，导致过氧亚硝酸盐（ONOO-）的形成，这可能引起病理生理效应，包括蛋白质的酪氨酸硝化。因为两者都没有。和POGI2具有相似的功能，并受到相同的炎症细胞因子的刺激，我们和其他人假设NO。通过与启动这一过程的酶，前列腺素H2合成酶（PGHS，也称为环氧合酶）的直接相互作用来促进花生四烯酸的代谢。氮氧化物的一种形式，即ONOO-，激活PGHS-1，另一种形式，NO。，抑制PGHS-1活性。Nox调节PGHS活性的机制尚不明确。我们在Specific Aim 1中设计了实验来解决这些作用机制。由于氮氧化物也可以通过激活导致血管细胞中花生四烯酸释放的信号分子来调节花生四烯酸的代谢，因此在Specific Aim 2中，研究旨在表征氮氧化物对导致花生四烯酸动员的信号级联反应的影响。最后，虽然ONOO-最初激活PGHS，它也有助于生物损伤。脉管系统最初可能使用PGHS来解毒ONOO-；并在此过程中合成有利于恢复血管止血的类二十烷酸。然而，随着疾病的进展，生物靶点发生氧化，如蛋白质的酪氨酸硝化，导致功能丧失。在Specific Aim 3中，我们提出表征PGHS在动脉粥样硬化斑块中的硝化程度。这些实验是我们以前工作的自然延伸，我们将继续利用我们其他PPG研究人员的才能。Gross, Hempstead, Silverstein)来推进这些目标。

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.