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 I2 (PGI2), both spontaneous and thrombin-induced, in terms of 6-oxo-PGF1α 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. 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-PGF1α 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. In the vascular tissue, prostaglandin I2 (PGI2, also called prostacyclin) is mainly produced by endothelial cells (ECs), and it generally counteracts the biological effects of thromboxane (Tx) A2. PGI2 inhibits platelet aggregation, relaxes vascular smooth muscle, and inhibits monocyte migration, lymphocyte adhesion, and smooth muscle cell (SMC) proliferation. Unlike nitric oxide, PGI2 does not regulate the systemic circulation constitutively, and more likely functions on demand in response to local stimuli (1Vila L Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall: role in atherosclerosis.Med. Res. Rev. 2004; 24: 399-424Crossref PubMed Scopus (94) Google Scholar). PGH2, formed from arachidonic acid (AA) by the catalytic action of cyclooxygenase (COX), is the common intermediate in the biosynthesis of two series of prostanoids. Two isoforms of COX have been fully characterized in humans to date. In general, COX-1 can be viewed as a constitutive enzyme, and prostanoids formed through the action of COX-1 mediate the so-called housekeeping functions, such as the regulation of renal function, maintenance of gastric mucosa integrity, and hemostasis. COX-2 is normally expressed in a number of tissues and cell types, such as endothelium or renal macula densa. However, it is induced in response to hormones, growth factors, pro-inflammatory cytokines, bacterial endotoxin, and tumor promoters, and is typically overexpressed at inflammatory sites, such as atherosclerotic lesions (as reviewed in Refs. 1Vila L Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall: role in atherosclerosis.Med. Res. Rev. 2004; 24: 399-424Crossref PubMed Scopus (94) Google Scholar, 2Bishop-Bailey D. Mitchell J.A. Warner T.D. COX-2 in cardiovascular disease.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 956-958Crossref PubMed Scopus (47) Google Scholar, 3Martinez-Gonzalez J. Badimon L. Mechanisms underlying the cardiovascular effects of Cox-inhibition: benefits and risks.Curr. Pharm. Des. 2007; 13: 2215-2227Crossref PubMed Scopus (89) Google Scholar). The enzyme catalyzing the conversion of PGH2 into PGI2 is PGI synthase (PGIS, prostacyclin synthase). PGIS is a membrane-bound hemoprotein located in the endoplasmic reticulum, and according to its spectral characteristics, is a cytochrome P450 protein (4Ullrich V. Castle L. Weber P. Spectral evidence for the cytochrome P450 nature of prostacyclin synthase.Biochem. Pharmacol. 1981; 30: 2033-2036Crossref PubMed Scopus (83) Google Scholar). Tyrosine-nitrating agents such as peroxynitrite and tetranitromethane cause tyrosine nitration and PGIS inactivation (5Zou M.H. Ullrich V. Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase.FEBS Lett. 1996; 382: 101-104Crossref PubMed Scopus (205) Google Scholar, 6Zou M.H. Martin C. Ullrich V. Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite.Biol. Chem. 1997; 378: 707-713Crossref PubMed Scopus (272) Google Scholar). Activity of PGIS is also controlled by substrate-dependent suicide inactivation (7Wade M.L. Voelkel N.F. Fitzpatrick F.A. “Suicide” inactivation of prostaglandin I2 synthase: characterization of mechanism-based inactivation with isolated enzyme and endothelial cells.Arch. Biochem. Biophys. 1995; 321: 453-458Crossref PubMed Scopus (31) Google Scholar). After treating human umbilical vein endothelial cells (HUVECs) with pro-inflammatory stimuli such as interleukin 1β (IL-1β), we observed that PGIS is inactivated faster in IL-1β-treated cells than in resting cells (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar, 9M Camacho Vila L. Transcellular formation of thromboxane A2 in mixed incubations of endothelial cells and aspirin-treated platelets strongly depends on the prostaglandin I-synthase activity.Thromb. Res. 2000; 99: 155-164Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Inactivation dependent on hydroxyl and NO2 radicals could also account for PGIS inactivation in inflammatory conditions (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar, 10Soler M. Camacho M. Molins-Pujol A.M. Vila L. Effect of an imidazolineoxyl N-oxide on prostaglandin synthesis in experimental shock: possible role of nitrogen dioxide in prostacyclin-synthase inactivation.J. Infect. Dis. 2001; 183: 105-112Crossref PubMed Scopus (15) Google Scholar). Many aspects of cardiovascular disease have traditionally been explained on the basis of disturbances in the TXA2 and PGI2 balance. Nevertheless, depending on the activity ratio of COX to PGIS, ECs could release untransformed PGH2 (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar, 9M Camacho Vila L. Transcellular formation of thromboxane A2 in mixed incubations of endothelial cells and aspirin-treated platelets strongly depends on the prostaglandin I-synthase activity.Thromb. Res. 2000; 99: 155-164Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 11Soler M. Camacho M. Escudero J.R. Iñiguez M.A. Vila L. Human vascular smooth muscle cells but not endothelial cells express prostaglandin E synthase.Circ. Res. 2000; 87: 504-507Crossref PubMed Scopus (99) Google Scholar). The biological activities of PGH2 are identical to those of TXA2, because both bind to the same receptor. COX-2 selective inhibitors reduce circulating PGI2 levels, indicating that COX-2 is involved in systemic production of PGI2 (12McAdam B.F. Castella-Lawson F. Mardini I.A. Kapoor S. Lawson J.A. Fitzgerald G.A. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2.Proc. Natl. Acad. Sci. USA. 1999; 96: 272-277Crossref PubMed Scopus (1201) Google Scholar). COX-2 is present after vascular damage and is highly expressed in atherosclerotic lesions and aortic aneurysms in animal models and human tissue (2Bishop-Bailey D. Mitchell J.A. Warner T.D. COX-2 in cardiovascular disease.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 956-958Crossref PubMed Scopus (47) Google Scholar). It probably plays a protective role in moderate vascular inflammation, promoting PGI2 biosynthesis. Nevertheless, the scenario could be different if COX-2 were highly expressed in a severely inflamed area, potentially producing large amounts of other prostanoids, such as PGE2 or PGH2 (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar, 13M Camacho Gerbolés, J. R. Escudero, R. Antón, X. García-Moll, and L. Vila E. Microsomal-PGE synthase-1, which is not coupled to a particular COX-isoenzyme, is essential for PGE2 biosynthesis in vascular smooth muscle cells.J. Thromb. Haemost. 2007; 5: 1411-1419Crossref PubMed Scopus (51) Google Scholar). Natural and synthetic derivatives of vitamin A (retinoids) exert profound effects on growth, maturation, and differentiation of many cell types (14Luca De M L. Retinoids and their receptors in differentiation, embryogenesis, and neoplasia.FASEB J. 1991; 5: 2924-2933Crossref PubMed Scopus (816) Google Scholar), and are currently used in cancer and several dermatological disease therapies (15Muindi J.R. Frankel S.R. Huselton C. DeGrazia F. Garland W.A. Young C.W. Warrell R.P. 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Retinoic exert effects on cells to and retinoic acid PubMed Scopus Google for to the of of 13-cis-RA for 6-oxo-PGF1α of was analyzed by enzyme the were with the species of RA with or for the of were with of at for was and were at 6-oxo-PGF1α by were with 13-cis-RA or for the of COX activity was evaluated by cells with for as (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar). COX activity was evaluated as the of all to eicosanoids formed through the COX PGIS activity was evaluated as (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar). of eicosanoids was as in a J. Vila L. L. in the formation of by Full Text PDF PubMed Scopus Google Scholar). mRNA expression, cells were with of the species of RA for the of and was mRNA expression was evaluated by real-time PCR as Camacho Gerbolés, J. R. Escudero, R. Antón, X. García-Moll, and L. Vila E. Microsomal-PGE synthase-1, which is not coupled to a particular COX-isoenzyme, is essential for PGE2 biosynthesis in vascular smooth muscle cells.J. Thromb. Haemost. 2007; 5: 1411-1419Crossref PubMed Scopus (51) Google Scholar). The of was to as and of cells was used as a of cells were as M. R. M. Vila L. the ability of umbilical vein endothelial cells to Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). protein of were to and for Western as Camacho Gerbolés, J. R. Escudero, R. Antón, X. García-Moll, and L. Vila E. Microsomal-PGE synthase-1, which is not coupled to a particular COX-isoenzyme, is essential for PGE2 biosynthesis in vascular smooth muscle cells.J. Thromb. Haemost. 2007; 5: 1411-1419Crossref PubMed Scopus (51) Google Scholar). A of PGIS was by A and an were to the and respectively. The was into the and the HUVECs were as C. J. Badimon L. of inhibit and expression in vascular endothelial 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). were with of the of and of The were to the cells for The was by or growth and for to the of RA in the or of of RAR antagonists for activity was in cell the and a the Results were by activity the was from from not for to the as L. C. J. L. C. J. M. Cyclooxygenase activity is increased in platelets from 1991; Full Text PDF PubMed Scopus Google Scholar). was to with for In platelet in response to AA was in an as L. C. J. L. C. J. M. Cyclooxygenase activity is increased in platelets from 1991; Full Text PDF PubMed Scopus Google Scholar, L. C. C. and J. C. In response of platelets with to of Scholar). to of was to of and to at for The ratio of platelet to was in and of platelet was observed the ratio was than of the of The ratio was for experiments with HUVECs with and in those experiments with HUVECs with the of in of was for after of AA The the was the results were expressed as of the the to the the with platelets HUVECs used in were by cells with cell of cell 13-cis-RA for for or 13-cis-RA for After the were and at for with acid to their and to was used for of was and was used for more than two A was the effect of 13-cis-RA on the release of PGI2 terms of by 13-cis-RA an increase in PGI2 in the with 13-cis-RA also increased PGI2 cells were with induced COX-2 expression not the response of cells to a after the with 13-cis-RA in the or of several was and cells were with for a of 6-oxo-PGF1α in the was The results in that in 13-cis-RA increased the ability of HUVECs to both and in with in a effect of 13-cis-RA was with an of the ability of HUVECs to inhibit platelet induced by AA The effect was observed in both and IL-1β-treated In it was that in of experiments in which HUVECs were with 13-cis-RA inhibited platelet aggregation. of platelet in the of and IL-1β-treated of 13-cis-RA on the release of PGI2 by HUVECs in response to HUVECs were or with of 13-cis-RA in the or in the of of for the of was and cells with of for in the were analyzed by with of 13-cis-RA on platelet in response to of to of mixed of AA HUVECs with HUVECs with HUVECs with 13-cis-RA and in but HUVECs with of the the of in platelets as in of the the of in platelets as in are from experiments and the arachidonic endothelial of by HUVECs was fully inhibited by the with not with the effect on platelet of HUVECs conditions effect was more with HUVECs to HUVECs were with with their effect on platelet HUVECs were also to 13-cis-RA 13-cis-RA did not COX activity or COX expression In contrast, PGIS expression in terms of and enzyme activity was increased by the of HUVECs to 13-cis-RA in a expression and enzyme activity increased at of to 13-cis-RA synthase (PGIS) expression and PGIS activity as a of of of HUVECs to HUVECs were with of 13-cis-RA for the of PGIS mRNA protein and activity were determined as in and The of was to as and of cells was used as a A of with of PGIS are and with cells the effect on PGIS expression in HUVECs for to several RA were to induce PGIS expression. In contrast, which RAR showed effect on the of PGIS mRNA or an did not the effect of 13-cis-RA on PGIS expression, an RAR inhibited the effect of 13-cis-RA Results in that both D and cycloheximide the effect of 13-cis-RA on PGIS protein expression, that RA PGIS in ECs through a transcriptional In in transient transfection a of PGIS 13-cis-RA increased PGIS activity was inhibited by but not by of 13-cis-RA on PGIS transcriptional HUVECs were with a of the PGIS after cells were with 13-cis-RA for in the or of or and cells were for of Results are the of two experiments by cells with 13-cis-RA RA plays an role in the of the cardiovascular M.L. R. J. of a retinoic acid receptor and in 1997; PubMed Scopus (89) Google and angiogenesis M. P. V. Effect of and on the formation of of human endothelial cells in is to 1998; PubMed Google Scholar). It also several biological activities that the synthesis of V. F. P. acid nitric oxide synthesis by endothelial Res. PubMed Scopus Google and inhibit the action of vasoconstrictor agents J. M. C. M. Retinoic acid expression at the in endothelial 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, V. S. E. J. Retinoids inhibit the of on vascular smooth muscle Res. 2001; PubMed Scopus Google Scholar, M. M. S. of thromboxane receptor expression by in vascular smooth muscle Res. 26: PubMed Scopus Google Scholar). In it exhibits and M. D. retinoic acid endothelial cell Google Scholar, Retinoic acid of monocyte tissue and tissue dependent 1995; PubMed Google Scholar, J. J. M. C. of acid on endothelial cell in and in J. 1991; Google Scholar, F. inhibits in 1995; 96: PubMed Scopus Google Scholar, R. acid formation and of the 1998; PubMed Scopus (83) Google Scholar, P. Retinoic acid smooth muscle cell and in and in through an Thromb. Vasc. Biol. 1999; PubMed Scopus Google Scholar, J. R. Retinoic acid and vessel 1999; PubMed Scopus Google Scholar, J.A. M. acid after in the a effect on vessel Thromb. Vasc. Biol. 2000; PubMed Scopus Google Scholar, acid vein and activity in Res. 2000; Full Text PDF PubMed Scopus Google Scholar, C.W. acid formation with of in Sci. 2000; PubMed Scopus Google Scholar, C. M. S. M. C. of local acid on experimental in the Res. PubMed Scopus Google Scholar). In of all these and synthetic are used as and The present that RA the ability of ECs to PGI2. The that 13-cis-RA increased the of 6-oxo-PGF1α in the and in response to COX expression and activity that it a action on the PGI2 In in HUVECs with which induced COX-2 but not PGIS expression 13-cis-RA increased the ability of HUVECs to PGI2. These results are in with that PGIS could be the enzyme for PGI2 inflammatory COX activity is increased to COX-2 expression (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar, 9M Camacho Vila L. Transcellular formation of thromboxane A2 in mixed incubations of endothelial cells and aspirin-treated platelets strongly depends on the prostaglandin I-synthase activity.Thromb. Res. 2000; 99: 155-164Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). RA PGIS expression, PGI2 biosynthesis. These were with the that the ability of HUVECs with RA to inhibit platelet in both IL-1β-treated and In contrast, was to the effect of HUVECs on platelet ECs were with These results that other than prostanoids were involved in the of platelet aggregation, HUVECs with was with that in by several with a role of endothelial nitric oxide and with a of biosynthesis in effect and L. Vila M. N-oxide the of vascular by interleukin-1β through several Infect. Dis. PubMed Scopus Google Scholar). In of the present it that the effect of RA on of platelet was strongly dependent on biosynthesis with both resting and IL-1β-treated other be present are with a an increase of PGI2 in ECs with 13-cis-RA and but not with of on endothelial cell prostacyclin production and platelet Sci. Full Text PDF PubMed Scopus Google Scholar), and also with a an increase in PGI2 in ECs with by through a mechanism of COX expression Retinoic acid effects on endothelial cell with interleukin PubMed Scopus Google Scholar). In the present we for the that RA PGIS expression in terms of mRNA and which with an increase in PGIS enzyme The that the action of 13-cis-RA on PGIS was at the transcriptional was by the that both D and cycloheximide the effect of 13-cis-RA on PGIS protein expression. concept is by the results of transfection The that and which bind to RAR and PGIS expression but not which RAR the that the RA action was mediated by receptors of 13-cis-RA RAR with conversion to and of was by the that did not the effect of 13-cis-RA on PGIS expression, RAR inhibited the expression of PGIS by of RAR was also by transfection in which 13-cis-RA increased PGIS transcriptional activity, to a than mRNA as in transient transfection J. J. J. Badimon L. is involved in endothelial cell 2006; Full Text Full Text PDF PubMed Scopus Google Scholar), and that it was inhibited by results that RA PGIS expression through a transcriptional mechanism mediated by RAR. However, RAR response were in the PGIS by in have the of by RA and RAR. RA can exert a of receptors such as receptor effects of retinoic acid on cell growth from of two different 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), and the of several and pathways involved in cell functions been T.D. of by retinoic Sci. 83: PubMed Scopus Google Scholar, S. Retinoic through retinoid receptors from cell by of and protein 2007; PubMed Scopus Google Scholar, M. M. M. S. S. R. acid inhibits through the 2007; PubMed Scopus Google Scholar, of transcriptional and the protein with the retinoic acid response of and in cells.J. Biol. 2007; PubMed Scopus Google Scholar). Furthermore, because other than have been with effects J. A retinoic retinoic Biol. 2004; 24: PubMed Scopus Google Scholar), or could be involved in the of PGIS by experiments are to the involved in the regulation of PGIS by have a of biological activities that are PGI2 is a that plays an role in vascular as a (1Vila L Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall: role in atherosclerosis.Med. Res. Rev. 2004; 24: 399-424Crossref PubMed Scopus (94) Google Scholar). It also an effect in A.M. of prostacyclin synthase expression Res. Google Scholar). of could be a for selective We have that the and ratio released by ECs depends on the activity ratio (8Camacho M. López-Belmonte J. Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and PGI-synthase activity.Circ. Res. 1998; 83: 353-365Crossref PubMed Scopus (124) Google Scholar, 9M Camacho Vila L. Transcellular formation of thromboxane A2 in mixed incubations of endothelial cells and aspirin-treated platelets strongly depends on the prostaglandin I-synthase activity.Thromb. Res. 2000; 99: 155-164Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 11Soler M. Camacho M. Escudero J.R. Iñiguez M.A. Vila L. Human vascular smooth muscle cells but not endothelial cells express prostaglandin E synthase.Circ. Res. 2000; 87: 504-507Crossref PubMed Scopus (99) Google Scholar). that RA selectively PGIS expression and activity, which results in an increase in the activity ratio that to a in PGI2 biosynthesis. results to the concept that RA could be beneficial for vascular in patients with cardiovascular and in cancer The for