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Peroxynitrite provides the peroxide tone for PGHS‐2‐dependent prostacyclin synthesis in vascular smooth muscle cells
Author(s) -
Schildknecht Stefan,
Bachschmid Markus,
Ullrich Volker
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3465fje
Subject(s) - peroxynitrite , chemistry , prostacyclin , vascular smooth muscle , biochemistry , nitric oxide , prostaglandin , enzyme , biophysics , microbiology and biotechnology , endocrinology , superoxide , biology , smooth muscle , organic chemistry
Endotoxin‐treated vascular smooth muscle cells (VSMCs) were recently shown to release high amounts of prostacyclin (PGI 2 ) dependent on the induction of prostaglandin endoperoxide synthase‐2 (PGHS‐2). In contrast to endothelial PGI 2 ‐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 PGI 2 release by VSMC. The hypothesis of peroxynitrite supplementing an unsaturated peroxide tone for PGHS‐2 was supported by H 2 O 2 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 • O 2 − , which together form peroxynitrite, while excessive production of either one radical was inhibitory. Most importantly, 6‐keto‐PGF 1α formation by intact VSMC depended on a nearly equimolar generation of • NO and • O 2 − 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 PGI 2 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.