title: Retinoic acid induces PGI synthase expression in human endothelial cells.
abstract: Retinoic acid (RA) exhibits anti-inflammatory, anti-tumor, and immuno-modulatory actions, and affects angiogenesis and thrombosis. Arachidonic acid (AA) metabolites are involved in all these processes. We explored the effect of RA on AA metabolism in human umbilical vein endothelial cells (HUVECs). 13-cis-RA increased the release of prostaglandin I(2) (PGI(2)), both spontaneous and thrombin-induced, in terms of 6-oxo-PGF(1alpha) analyzed by enzyme-immunoassay. Coincubation with 13-cis-RA and interleukin-1beta resulted in a synergic increase in the release of PGI(2). Consistently, 13-cis-RA increased the ability of HUVECs to inhibit AA-induced platelet aggregation. 13-cis-RA did not induce cyclooxygenase-isoenzyme expression, determined by immunoblotting, or activity, evaluated by analyzing eicosanoids formed from exogenous labeled AA by HPLC. In contrast, RA induced PGI synthase (PGIS) activity and expression in terms of mRNA and protein determined by real-time PCR and Western blotting, respectively. Results from experiments with several species of RA and with retinoic acid receptor (RAR) and retinoid X receptor (RXR) antagonists showed that the effect of RA on PGIS expression was mediated by RAR. Actinomycin D and cycloheximide both inhibited RA-induced PGIS expression. Furthermore, RA increased PGIS transcriptional activity in transient transfection assays, an effect that was prevented by an RAR antagonist. These results reinforce the concept that RA could be beneficial for patients with cardiovascular risk.
authors.affiliation: Angiology, Vascular Biology, and Inflammation Laboratory of the Institute of Research, Hospital Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Camacho
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.forename: Juliana
authors.initials: J
authors.lastname: Salazar
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.forename: Josep
authors.initials: J
authors.lastname: Ribalta
authors.forename: José-Román
authors.initials: JR
authors.lastname: Escudero
authors.forename: Lluís
authors.initials: L
authors.lastname: Masana
authors.forename: Luis
authors.initials: L
authors.lastname: Vila
mesh_terms: D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004790:Enzyme Induction; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis*; D015474:Isotretinoin / Q000494:pharmacology*
chemical_list: D003609:Dactinomycin; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D015474:Isotretinoin