Retinoic acid induces PGI-synthase expression in human endothelial cells

Mercedes Camacho, Cristina Rodríguez, Juliana Salazar, José Martínez-Gonzalez, Josep Ribalta, José-Román Escudero, Lluis Masana, and Luis Vila

Lab. Angiology, Vascular Biology and Inflammation, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Barcelona 08025

Corresponding Author: 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 (HUVEC). 13-cis-RA increased the release of PGI₂, both spontaneous and thrombin-induced, in terms of 6-oxo-PGF_1{alpha} analyzed by enzyme-immunoassay. Co-incubation with 13-cis-RA and IL-1 $beta$ resulted in a synergic increase in the release of PGI₂. Consistently, 13-cis-RA increased the ability of HUVEC to inhibit AA-induced platelet aggregation. 13-cis-RA did not induce COX-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 RAR and 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 a RAR antagonist. These results reinforce the concept that RA could be beneficial for patients with cardiovascular risk.

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