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Journal of Lipid Research, Vol. 49, 1707-1714, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Retinoic acid induces PGI synthase expression in human endothelial cells

Mercedes Camacho^*, Cristina Rodríguez, Juliana Salazar, José Martínez-González, Josep Ribalta, José-Román Escudero^**, Lluís Masana and Luis Vila^1,*

^* Angiology, Vascular Biology, and Inflammation Laboratory of the Institute of Research, Hospital Santa Creu i Sant Pau, Barcelona, Spain
^** Vascular Surgery Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain
Cardiovascular Research Center, CSIC-ICCC is Consejo Superior de Investigaciones Científicas-Intitut Català de Ciències Cardiovasculars, Barcelona, Spain
Atherosclerosis and Lipid Research Unit, Universitat Rovira I Virgili, Reus, Spain

This work was supported by grants from the Fondo de Investigaciones Sanitarias (C/03/08, G/03/181, G/03/140, FIS02/0396, and RECAVA-RD06/0014) and from the Ministerio de Educación y Ciencia (SAF 2001-02781 and SAF 2005-04549).

Published, JLR Papers in Press, May 5, 2008.

¹ To whom correspondence should be addressed. e-mail: lvila{at}santpau.cat

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 I₂ (PGI₂₎, both spontaneous and thrombin-induced, in terms of 6-oxo-PGF₁ analyzed by enzyme-immunoassay. Coincubation with 13-cis-RA and interleukin-1β resulted in a synergic increase in the release of PGI₂. 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.

Supplementary key words prostacyclin synthase • prostaglandin I₂ • retinoic acid receptor • cyclooxygenase pathway

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