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Peroxynitrite provides the peroxide tone for PGHS‐2‐dependent prostacyclin synthesis in vascular smooth muscle cells

Endotoxin‐treated vascular smooth muscle cells (VSMCs) were recently shown to release high amounts of prostacyclin (PGI2) dependent on the induction of prostaglandin endoperoxide synthase‐2 (PGHS‐2). In contrast to endothelial PGI2‐synthase, for which nitration and inhibition by peroxynitrite was reported, addition of SIN‐1 as a peroxynitrite‐generating system did not cause inhibition but rather doubled PGI2 release by VSMC. The hypothesis of peroxynitrite supplementing an unsaturated peroxide tone for PGHS‐2 was supported by H2O2 exerting the same effect. Studies performed with purified PGHS‐2 revealed maximal elevation of enzyme activity in the presence of equimolar concentrations of •NO and •O2−, which together form peroxynitrite, while excessive production of either one radical was inhibitory. Most importantly, 6‐keto‐PGF1α formation by intact VSMC depended on a nearly equimolar generation of •NO and •O2− for providing the endogenous peroxide tone. These findings, together with the observation that an excess of exogenously added •NO, as well as uric acid as a scavenger of peroxynitrite potently reduced PGI2 release, underlined the role of peroxynitrite as the dominating and rate‐limiting intracellular mediator of peroxide tone in VSMC. The results allow us to postulate a new cross‐talk between the •NO and the prostanoid pathways with a crucial role for peroxynitrite in providing the peroxide tone for a continuous activation of PGHS‐2.