Peroxynitrite as regulator of vascular prostanoid synthesis

Prostanoids and nitric oxide ((.)NO) are essential modulators of cardiovascular function in health and disease. Among the (.)NO-derived species formed in cells, peroxynitrite (ONOO(-)) is generally associated with its role as nitrating agent under severe pathophysiological conditions. This review, however, highlights a physiological role of peroxynitrite as endogenously formed regulator of prostanoid synthesis in the cardiovascular system. Prostaglandin endoperoxide H2 synthase (PGHS)(1), the central enzyme in the prostanoid pathway was observed to be nitrated and inactivated by high fluxes of peroxynitrite. In contrast, low nanomolar levels, that are formed endogenously in cardiovascular cells, turned out to activate PGHS and therefore prostanoid formation. A further increase in the rates of (.)NO and superoxide ((.)O2(-)) generation, that can be observed after exposure of vascular endothelial cells to endotoxin, results in enhanced levels of peroxynitrite that were shown to selectively nitrate and inactivate prostacyclin (PGI(2))-synthase as one of the dominating terminal prostanoid synthases in the cardiovascular system. As a consequence, accumulation of the intermediate PGH(2) occurs that is capable to activate the thromboxane A(2) (TxA(2)) receptor on the surface of smooth muscle cells to promote vasoconstriction. The nitration of PGI(2)-synthase thus functions as endogenous posttranslational switch that shuts off the PGI(2)-mediated vasodilatory, anti-aggregatory, and anti-adhesive conditions in order to support the transmigration of immune cells from the blood to the sites of an infection. As a third type of interaction between the (.)NO and the prostanoid pathways, an activation of nitrite by the endogenous peroxidase activity of PGHS can lead to an autocatalytic nitration and inactivation of PGHS under conditions of high nitrite and low arachidonic acid levels that mostly prevail in progressive activation stages in cell types that express inducible NOS-2 such as macrophages.