Imidazolineoxyl N-oxide induces COX-2 in endothelial cells:  role of free radicals.
cPTIO (2-[4-carboxyphenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) exerts beneficial actions on systemic inflammatory response. Besides its nitric oxide (NO) scavenging properties cPTIO could exert beneficial effects through modulation of arachidonic acid metabolism. We studied the effect of cPTIO on the biosynthesis of vasoactive prostaglandins (PG) by endothelial cells. Human cord umbilical vein endothelial cells (HUVEC) were treated with cPTIO, and expression of cycloxygenase (COX) isoenzymes in terms of mRNA and protein was determined by real-time-PCR and immunoblotting. Release of PGE2 (as index of untransformed PGH2 release) and 6-oxo-PGF1alpha (PGI2 stable metabolite) was determined by enzyme-immunoassay. cPTIO significantly increases the release of untransformed PGH2 associated to the induction of COX-2 expression. Experiments with NO-synthase inhibitors and radical scavengers showed that induction of COX-2 by cPTIO was mediated by free radical species, likely caused by the mobilization of NO from cellular stores. Finally, using specific signal-transduction inhibitors we show the involvement of Src/PI3-K/PKC pathway. Additional effects other than a direct NO scavenging activity may confer therapeutic advantages to cPTIO as compared with NO-synthase inhibitors for the treatment of systemic inflammation-associated vascular hyporeactivity.
Laboratory of Angiology, Vascular Biology and Inflammation, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain.
Mercedes
M
Camacho
Jose
J
Martinez-Gonzalez
Cristina
C
Rodriguez
Laura
L
Siguero
Cristina
C
Seriola
Jose-Maria
JM
Romero
Luis
L
Vila
D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004790:Enzyme Induction; D005609:Free Radicals; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D001565:Benzoates; D005609:Free Radicals; D007093:Imidazoles; D017382:Reactive Oxygen Species; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D051546:Cyclooxygenase 2; D015232:Dinoprostone