doi: 10.1161/hq1101.098488
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Biphasic Effects of 15-Deoxy-
12,14-Prostaglandin J2 on Glutathione Induction and Apoptosis in Human Endothelial Cells
From the Department of Pathology, Molecular and Cellular Division (A.-L.L., D.R.M., V.M.D.-U.), Center for Free Radical Biology (H.J.F., V.MD-U), and the Department of Environmental Health Sciences, School of Public Health (D.A.D., H.J.F.), University of Alabama at Birmingham, and the Department of Pharmacology (R.T.M), University of Wisconsin-Madison.
Correspondence to Dr Victor M. Darley-Usmar, Department of Pathology, Molecular and Cellular Division, University of Alabama at Birmingham, Volker Hall Room G038, 1670 University Blvd, Birmingham, AL 35294-0019. E-mail darley{at}path.uab.edu
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Abstract |
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Abstract—— The lipid products derived from the cyclooxygenase pathway can have diverse and often contrasting effects on vascular cell function. Cyclopentenone prostaglandins (cyPGs), such as 15-deoxy-
12,14-prostaglandin-J2 (15d-PGJ2), a peroxisome proliferator–activated receptor-
(PPAR) agonist, have been reported to cause endothelial cell apoptosis, yet in other cell types, cyPGs induce cytoprotective mediators, such as heat shock proteins, heme oxygenase-1, and glutathione (GSH). Herein, we show in human endothelial cells that low micromolar concentrations of 15d-PGJ2 enhance GSH-dependent cytoprotection through the upregulation of glutamate-cysteine ligase, the rate-limiting enzyme of GSH synthesis, as well as GSH reductase. The effect of 15d-PGJ2 on GSH synthesis is attributable to the cyPG structure but is independent of PPAR, inasmuch as the other cyPGs, but not PPAR or PPAR
agonists, are able to increase GSH. The increase in cellular GSH is accompanied by abrogation of the proapoptotic effects of 4-hydroxynonenal, a product of lipid peroxidation present in atherosclerotic lesions. However, higher concentrations of 15d-PGJ2 (10 µmol/L) cause endothelial cell apoptosis, which is further enhanced by depletion of cellular GSH by buthionine sulfoximine. We propose that the GSH-dependent cytoprotective pathways induced by 15d-PGJ2 contribute to its antiatherogenic effects and that these pathways are distinct from those leading to apoptosis.
Key Words: cyclopentenone prostaglandins • glutathione • glutamate-cysteine ligase • endothelium • apoptosis
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Introduction |
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Prostaglandins of the J series (PGJs) are cyclopentenones synthesized from arachidonic acid via enzymatic conversion by cyclooxygenase and prostaglandin D2 (PGD2) synthase, followed by nonenzymatic dehydration of PGD2 to PGJ2,
12-PGJ2, and 15-deoxy-12,14-PGJ2 (15d-PGJ2).1 These compounds have generated considerable interest in vascular biology after the discovery of their ability to activate one of the ligand-activated nuclear receptors, peroxisome proliferator–activated receptor- (PPAR).2 Through a mechanism in which 15d-PGJ2 acts as a PPAR agonist, it has been shown to inhibit production of proinflammatory cytokines in monocytes and the binding of these cells to the endothelium.3,4 However, cyclopentenone prostaglandins (cyPGs) have also PPAR-independent anti-inflammatory effects, including inhibition of nuclear factor-
B activation by inhibiting IB kinase.5,6 This is important in atherogenesis, because some of the early events in lesion formation, such as monocyte recruitment and adherence, are mediated by nuclear factor-B–dependent upregulation of monocyte chemoattractant protein-1, as well as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1.7 Moreover, cyPGs induce cytoprotective mediators, such as heat shock proteins, heme oxygenase-1, and glutathione (GSH), further strengthening the notion that cyPGs are potentially antiatherogenic.8–10 However, cyPGs have also been shown to be cytostatic or cytotoxic to a number of cell types, including endothelial cells, vascular smooth muscle cells, and monocytes.11–14 Apoptosis caused by 15d-PGJ2 in endothelial cells has been reported to be PPAR dependent,11 whereas in a human neuroblastoma cell line, it has been proposed that the production of reactive oxygen species and secondary lipid peroxidation products leads to cell death.14 The diverse effects of the cyPGs on vascular cells remain uncertain and potentially conflicting. Although inhibition of vascular smooth muscle cell growth can be antiatherogenic, endothelial cell apoptosis, perturbation of the endothelial cell layer integrity, and subsequent leakage of LDL and other serum-derived factors into the subendothelial space would promote lesion formation.15
Clearly, it is important to examine the cytotoxic and cytoprotective aspects of these compounds to gain a perspective on the biological actions of cyPGs in the vasculature. In the present study, human endothelial cells were exposed to a range of concentrations of 15d-PGJ2 commonly used in the literature. In the present study, we show that low micromolar concentrations of 15d-PGJ2 cause a robust increase in cellular GSH through transcriptional upregulation of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis,16 via a mechanism independent of PPAR, whereas higher concentrations (10 µmol/L) cause endothelial cell apoptosis. Moreover, we show that low concentrations of 15d-PGJ2 confer resistance against cell death caused by 4-hydroxynonenal (HNE), a lipid peroxidation product found in atherosclerotic lesions.
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Methods |
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Materials
Prostaglandins and arachidonic acid were purchased from Cayman Chemicals. These were stored in 10 mmol/L aliquots in ethanol at -80°C and diluted immediately before use. Ciglitazone and WY-14,643 were from BioMol, and HNE was from Calbiochem. The other reagents were purchased from Sigma Chemical Co.
Cell Culture
Human umbilical vein endothelial cells (HUVECs) were purchased from Endothelial Cell Service Center (Dr Francois Booyse, Department of Medicine, University of Alabama at Birmingham) and cultivated in plastic ware coated with 0.05% gelatin/10 µg/mL fibronectin (Biomedical Technologies) in endothelial cell growth medium (Clonetics) supplemented with 10% FBS. The experiments were performed in the same media with 2% FBS. Cells were used at passages 3 to 7 at confluence.
Measurement of GSH, GSH Peroxidase, GSH Reductase, and GST Activities
Total GSH (GSH+glutathione disulfide [GSSG]),17 glutathione peroxidase (GPx),18 and glutathione reductase (GR)19 activities were measured as previously described. The GR activity in samples was compared with that of GR from Bakers Yeast (Sigma), and the specific activity was expressed as units per milligram protein, in which 1 U will reduce 1.0 µmol GSSG per minute at pH 7.6 and 25°C. Glutathione-S-transferase (GST) activity was measured by using 1-chloro-2,4-dinitrobenzene as substrate.20 The GSH/GSSG ratio was measured by high-performance liquid chromatography as in Moellering et al.19
RNA Analysis
Total RNA was extracted from HUVECs by using an RNeasy Mini Kit (Qiagen). Levels of mRNA for the catalytic (GCLC) and modifier (GCLM) subunits of GCL were quantified from 15 µg total RNA by the ribonuclease protection assay (RPA II, Ambion Inc), as in Levonen et al,21 with the use of GAPDH probe transcribed from human GAPDH cDNA clone digested with DdeI (pTRI-GAPDH-Human, Ambion Inc) to normalize for RNA content. The x-ray films were scanned with the FluorChem fluorescence detecting system and quantified by using AlphaEase FC software (Alpha Innotech Corp).
Western Blotting of GCLC and GCLM
Western blotting of cell lysates (10 µg) was performed as described by using antibodies specific to GCLC and GCLM.22 The membrane was developed by a chemiluminescent detection method, and quantification was performed on an AlphaImager (Alpha Innotech Corp).
Detection of Cell Death
Apoptosis was measured by labeling the cells with annexin V–FITC and propidium iodide and subsequent fluorescence-activated cell sorter analysis.23 Confluent HUVECs were treated with 15d-PGJ2 for indicated times. The cells were detached by using trypsin-EDTA, washed with PBS, and resuspended to 100 µL annexin V binding buffer, with 0.5 ng annexin V–FITC and 2.5 ng propidium iodide (Clontech). Cells (105) were analyzed on a FACScan (Becton Dickinson) with the use of WINMDI 2.8 software (The Scripps Research Institute Cytometry Software Page at http://facs.scripps.edu/software.html) within 30 minutes after staining.
Statistical Analysis
Results of the experimental studies are reported as mean±SEM. Differences were analyzed by Student t test. A difference between groups of P<0.05 was considered significant.
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Results |
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Effect of Prostaglandins, Arachidonic Acid, PPAR
, and PPAR Activators on GSHTotal cellular GSH was increased in HUVECs on exposure to prostaglandin A1 (PGA1), PGD2, PGJ2, and 15d-PGJ2 (Figure 1A). Of these compounds, PGA1, PGJ2, and 15d-PGJ2 have a cyclopentenone structure, whereas PGD2 converts nonenzymatically to PGJs.1 Prostaglandin E2 or arachidonic acid were not able to induce GSH, implying that the cyclopentenone structure is important for GSH induction.
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Because PGJs were the most potent inducers of GSH, we then examined the concentration and time-dependent induction of GSH by 15d-PGJ2. Incubation of HUVECs with 0.5 to 5 µmol/L 15d-PGJ2 for 16 hours caused an increase in GSH, which was significant with 0.5 µmol/L 15d-PGJ2 (Figure 1B). However, with 10 µmol/L 15d-PGJ2 or PGJ2, there was no difference in GSH versus control (Figure 1A and 1B). The increase in total GSH was significant after 8 hours of incubation with 5 µmol/L 15d-PGJ2 and occurred without a decrease in total GSH at the early time points (Figure 1C). The GSH/GSSG ratio (39±3 at 0 hours, n=3) did not change during incubation with a low concentration (2.5 µmol/L) of 15d-PGJ2 at 0.5 to 16 hours but was significantly increased at 24 hours (60±1, P<0.05; Figure 1D). Therefore, the increase in total GSH is largely due to changes in the reduced form. In contrast, with 10 µmol/L 15d-PGJ2, the GSH/GSSG ratio declined steadily (Figure 1D).
Next, we tested whether the induction of GSH by 15d-PGJ2 is mediated by PPAR. The PPAR agonist ciglitazone did not cause an increase in cellular GSH. On the contrary, ciglitazone caused a dose-dependent decrease in cellular GSH (30% and 46% decrease in total GSH with 10 and 20 µmol/L ciglitazone, respectively; P<0.05). At concentrations >40 µmol/L, ciglitazone was toxic to the cells. Neither of the PPAR activators, Wy-14,643 or fenofibrate up to 100 µmol/L, was able to change GSH levels to any significant extent (results not shown).
Effect of 15d-PGJ2 on the Expression of GCL
The cyclopentenone prostaglandin, PGA2, has been shown to increase cellular GSH in murine leukemia cells through the induction of GCL.8 To test whether GCL is induced in endothelial cells by 15d-PGJ2, we studied the mRNA expression of GCLC and GCLM by RPA. 15d-PGJ2 (5 µmol/L) caused a time-dependent induction of mRNAs for both GCL subunits, and GCLC was induced by 2-fold and GCLM was induced by 3-fold 6 hours after treatment (Figure 2A). The induction at 6 hours was already significant with 0.5 µmol/L 15d-PGJ2 (Figure 2B). Although the induction of either GCL subunit mRNA was smaller with 10 µmol/L 15d-PGJ2 than with 2.5 µmol/L or 5 µmol/L 15d-PGJ2, GAPDH expression was decreased as well, and the ratio of GCL mRNA to GAPDH did not change. This indicates that the decline in GCL mRNA expression was due to the cytotoxic effect and general decrease in transcription rather than specific downregulation of GCL with high concentrations of 15d-PGJ2. To determine whether the increase in GCL mRNA is attributable to a transcriptional induction, the cells were incubated with 15d-PGJ2 in the presence and absence of the transcriptional inhibitor actinomycin D (Figure 2C). Actinomycin D abolished the induction of GCL, implying that the induction of GCL subunits is transcriptional.
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Next, we studied the protein expression GCL of by Western blotting. 15d-PGJ2 caused a 2-fold induction of GCLM in 16 hours, whereas GCLC protein levels were not significantly changed at this time point (Figure 2D).
Effect of 15d-PGJ2 on Other GSH-Metabolizing Enzymes
To study the effects of 15d-PGJ2 on other GSH-metabolizing enzymes, we exposed the cells to 0.5 to 10 µmol/L 15d-PGJ2 for 16 hours and measured GPx, GST, and GR activities. Neither GPx nor GST was significantly changed by 15d-PGJ2 (results not shown). However, GR showed a concentration-dependent induction with 0.5 to 5 µmol/L 15d-PGJ2. The induction was significant at 0.5 µmol/L 15d-PGJ2 (0.23±0.01 U/mg protein versus control 0.16±0.01 U/mg protein, P<0.01; n=3) and was maximal at 2.5 to 5 µmol/L 15d-PGJ2 (0.32±0.01 U/mg protein), whereas 10 µmol/L 15d-PGJ2 decreased GR by 
25% (0.12±0.003 U/mg protein, P<0.05 versus control; n=3). Because synthesis of GSH is also dependent on the reuse of exported GSSG or GSH conjugates via -glutamyl transpeptidase (-GT),24 we studied the effect of the specific inhibitor of -GT, acivicin, on the induction of GSH by 15d-PGJ2. In the presence of 5 µmol/L acivicin, the percent increase in GSH on exposure to 15d-PGJ2 (5 µmol/L) for 16 hours was significantly smaller (174±17% versus 263±17% 15d-PGJ2 only, P<0.01; n=3), implying that -GT is important for the increase in intracellular GSH.
Effect of 15d-PGJ2 on Endothelial Cell Viability
Incubation of endothelial cells with 10 µmol/L 15d-PGJ2 or PGJ2 caused significant cytotoxic changes in endothelial cell morphology in the initial experiments. To assess cell death caused by 15d-PGJ2, endothelial cells were treated with increasing concentrations of 15d-PGJ2 with and without 250 µmol/L buthionine sulfoximine (BSO), a specific inhibitor of GCL, 24 hours before and during 16 hours of treatment with 15d-PGJ2. With this treatment regimen, GSH was decreased by 90%. Incubation with 10 µmol/L 15d-PGJ2 caused a significant (P<0.001) increase in the apoptotic (annexin V–FITC positive) cell population compared with untreated controls (Figure 3A). Although 5 µmol/L 15d-PGJ2 by itself caused no cytotoxicity, it did so in combination with BSO, and BSO also caused a significant exacerbation of the cytotoxicity of 10 µmol/L 15d-PGJ2 (Figure 3A).
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The possibility that lower nontoxic concentrations of 15d-PGJ2 that cause GSH induction could confer resistance against lipid peroxidation products associated with atherogenesis was also examined. To address this, HUVECs were first treated with 15d-PGJ2 for 24 hours, after which the cells were washed with HBSS and incubated further with HNE. This lipid peroxidation product has been shown to induce apoptosis in a number of cell types, including HUVECs,25,26 and it is present in human atherosclerotic lesions.27 Incubation with 15 µmol/L HNE caused a statistically significant (P<0.05 versus untreated control) increase in the apoptotic cell population. Incubation of cells with 2.5 µmol/L 15d-PGJ2 for 24 hours before HNE treatment attenuated cytotoxicity, and this effect was most striking with the highest concentration (20 µmol/L) of HNE (Figure 3B). The lowest concentration of 15d-PGJ2 that was protective was 0.5 µmol/L (Figure 3C). To assess the role of GSH on cytoprotection against HNE, the cells were treated with 1 µmol/L 15d-PGJ2 in the presence of 10 µmol/L BSO, which caused an 90% reduction of GSH versus 15d-PGJ2 alone. BSO decreased the cytoprotective effect of 15d-PGJ2 treatment (Figure 3C). BSO alone did not enhance the already substantial cytotoxicity of this concentration of HNE (Figure 3C).
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Discussion |
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In the present study, we demonstrate that 15d-PGJ2 has dual effects on endothelial cell survival and apoptosis. Low concentrations are cytoprotective via a mechanism that involves a major contribution from an increase in intracellular GSH, whereas higher concentrations are cytotoxic.
The concentrations of 15d-PGJ2 found at local sites of inflammation are not clear, because estimations are complicated by the reactivity of the ,ß-unsaturated carbonyl group characteristic to cyPGs, which renders them susceptible to conjugation.28 Thus, the low concentrations assessed in some biological settings do not necessarily represent the concentrations to which the cells are exposed at sites of inflammation.29,30 PGD2 synthesis has been shown to be upregulated in synthetic phenotype of smooth muscle cells in the atherosclerotic intima.31 It is plausible that in a pathophysiological setting, a wide range of concentrations of the PGJs can occur with a corresponding spectrum of biological responses. It should be noted, however, that although PGD2 readily undergoes dehydration into PGJs in the presence of albumin in vitro, the extent by which this occurs in vivo is still under debate because the studies have been focused on finding free PGJs rather than PGJ-protein adducts.28
In the present study, we show that 0.5 to 5 µmol/L 15d-PGJ2 causes an increase in cellular GSH, which is preceded by transcriptional upregulation of GCLM and GCLC mRNA (Figure 2A through 2C). However, changes in GCLC mRNA were not reflected in increased protein (Figure 2D). Nevertheless, a 2-fold upregulation of GCLM protein was observed. Although GCLC has all the catalytic activity and is feedback-inhibited by GSH, the light subunit has an important regulatory role, by decreasing the Ki for GSH, thereby increasing the catalytic activity.22,32 Therefore, increase in GCLM protein without changes in catalytic subunit expression is sufficient to increase GSH synthesis.
A strong candidate for mediating GCL induction by 15d-PGJ2 is the electrophile responsive element (EpRE). It is present in both GCL genes and accounts for basal transcriptional activity, as well as ß-naphthoflavone– and pyrrolidine dithiocarbamate–induced GCL expression.33,34 This element is activated on exposure to electrophiles through dissociation of transcription factor Nrf2 from its cytoplasmic docking protein Keap1 and the subsequent nuclear translocation and transactivation of EpRE.35,36 The actual mechanism of dissociation of Nrf2 from Keap1 is currently unknown, but it is thought to involve thiol modifications or phosphorylation of Keap1, Nrf2, or both.35–37 Thus, it is possible that 15d-PGJ2 binds to thiol groups, thereby activating Nrf2, or it may activate redox-sensitive kinase pathways and cause EpRE activation. Current studies in our laboratory are directed at elucidating the mechanism by which 15d-PGJ2 causes transcriptional induction of GCL and whether EpRE is involved.
15d-PGJ2 has been shown to inhibit GPx in the human neuroblastoma cells14 and induce GST in hepatoma cell lines.38 These activities were not significantly altered in endothelial cells (results not shown). However, GR activity was increased in a concentration-dependent manner with low concentrations of 15d-PGJ2. The regulation of GR is poorly known, but recently, a functional EpRE element has been found in its promoter region (R.T. Mulcahy, unpublished data, 2001). In the endothelium, the upregulation of GR activity may provide an additional mechanism to increase the level of reduced GSH.
In the present study, high concentrations of 15d-PGJ2 as well as another PPAR activator, ciglitazone, caused endothelial cell death. These results are consistent with previous reports demonstrating a PPAR-dependent increase in endothelial cell apoptosis.11 Recently, other, PPAR-independent, mechanisms of cytotoxicity of 15d-PGJ2 involving increased production of reactive oxygen species have been suggested.14 This would be consistent with the data showing that BSO enhanced the cytotoxicity of 15d-PGJ2 (Figure 3A). However, reactive oxygen species are not necessarily involved in the process, because GSH readily conjugates with 15d-PGJ2, thereby modulating its biological effects.28 Similarly, inhibition of the cytotoxicity of 15d-PGJ2 by thiol antioxidant N-acetylcysteine14 may be through conjugation, because 15d-PGJ2 reacts with low molecular weight thiols even in the absence of cells.28 Clearly, further studies are needed to define the mechanisms involved in endothelial cell apoptosis caused by 15d-PGJ2.
In the literature, up to 20 µmol/L 15d-PGJ2 has been used in human endothelial cells without appreciable cytotoxicity.39 It is difficult to compare the concentrations used in different studies, because 15d-PGJ2 is unstable, and the actual concentrations from commercial sources may vary.28 Another aspect that may explain some of the inconsistencies in the literature are different serum concentrations of the growth media, which have a major impact on the cytotoxicity of 15d-PGJ2 and thiazolidinediones.11,39
Oxidized derivatives of fatty acids are implicated in the pathogenesis of atherosclerosis. HNE, an aldehyde generated during oxidation of polyunsaturated fatty acids, is thought to be a major mediator of the adverse effects of lipid peroxidation.27 The proapoptotic effects of HNE are well documented in a number of cell types, including endothelial cells.25,26 In the present study, low concentrations of 15d-PGJ2 were protective against toxic effects of HNE. This effect was partially inhibited by BSO, suggesting that GSH contributes to the cytoprotective effects of 15d-PGJ2. Because cyPGs also induce other cytoprotective molecules such as heat shock proteins9 and heme oxygenase-1,10 these may play an additional role in cytoprotection.
Recent work by Taba et al29 have shown that shear stress induces lipocalin-type PGD2 synthase expression and increases the release of PGD2 and 15d-PGJ2 to the medium. Furthermore, shear stress activates enzymes involved in liberation of arachidonic acid and cyclooxygenase-2.29,40–42 Laminar shear stress has well-documented antiapoptotic effects,43,44 which have been shown to be mediated partially through GSH.44 Recently, we have shown that shear stress can increase GSH synthesis45; therefore, it will be of interest to assess the role of increased production of 15d-PGJ2 on GSH induction and cytoprotection by laminar flow.
In summary, we have shown that low nontoxic levels of 15d-PGJ2 cause a potent induction of cellular GSH through transcriptional upregulation of the rate-limiting enzyme, GCL, as well as GR. Moreover, preconditioning of endothelial cells with low concentrations of 15d-PGJ2 confers resistance against HNE cytotoxicity. We propose that the modulation of GSH-dependent cytoprotection by PGJs contributes to their antiatherogenic effects.
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Acknowledgments |
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This study was supported by National Institutes of Health (NIH) grants ES/HL-10167 and HL-58031 (V.M.D.-U.), National Institute of Health Environmental Health Sciences grant ES-09749 (R.T.M.), and NIH grant ES-05511 (H.J.F.). A.-L.L receives support from The Academy of Finland, The Finnish Foundation for Cardiovascular Research, and The Finnish Medical Society Duodecim.
Received June 1, 2001; accepted August 15, 2001.
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