Published online before print July 28, 2003, doi: 10.1161/01.HYP.0000085332.69777.D1
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(Hypertension. 2003;42:844.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
PPAR
Inhibition of Cyclooxygenase-2, PGE2 Synthase, and Inducible Nitric Oxide Synthase in Cardiac Myocytes
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
Correspondence to Margot C. LaPointe, PhD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689. E-mail mclapointe{at}aol.com
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Abstract |
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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They regulate lipid metabolism, glucose homeostasis, cell proliferation, and differentiation and modulate inflammatory responses. We examined whether PPAR
is functional in cultured neonatal ventricular myocytes and studied its role in inflammation. Western blots revealed PPAR in myocytes. When myocytes were transfected with a PPAR response element reporter plasmid (PPRE-TK-luciferase), the PPAR activator 15-deoxy-
12,14-prostaglandin J2 (15dPGJ2) increased promoter activity, whereas cotransfection of a dominant negative PPAR inhibited it. To determine the role of 15dPGJ2 in expression of proinflammatory genes, we tested its effect on interleukin-1ß induction of cyclooxygenase-2 (COX-2). 15dPGJ2 decreased interleukin-1ß stimulation of COX-2 by 40% and PGE2 production by 73%. We next questioned whether 15dPGJ2 was modulating the expression of inducible prostaglandin E2 synthase (PGES) and found that it completely blocked interleukin-1ß induction of PGES. Use of a second PPAR agonist, troglitazone, and the selective PPAR antagonist GW9662 demonstrated that the effects seen were PPAR-dependent. In addition, we found that 15dPGJ2 blocked interleukin-1ß stimulation of inducible nitric oxide synthase (iNOS). We concluded that 15dPGJ2 may play an anti-inflammatory role in a PPAR-dependent manner, decreasing COX-2, PGES, and PGE2 production, as well as iNOS expression.
Key Words: myocytes • nitric oxide synthase • cyclooxygenase • prostaglandins
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Introduction |
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Peroxisome proliferator-activated receptors (PPARs) are a family of 3 nuclear hormone receptors, PPAR
, PPARß (also named PPAR
), and PPAR, which are members of the steroid receptor superfamily. PPARs bind to cognate DNA elements called peroxisome proliferator response elements (PPRE) as obligate heterodimers with the retinoid X receptor (RXR). After ligand activation, they work as transcription factors.1,2 There are two PPAR subtypes, PPAR1 and PPAR2, which are derived from alternative splicing and promoter usage.3,4 PPAR2 is highly expressed in adipose tissue, whereas PPAR1 has been found in the kidney, heart, liver, and activated monocytes.5,6 PPAR can be activated by docosahexanoic acid and certain prostaglandins.7 Other PPAR ligands include the natural prostaglandin metabolite 15-deoxy-12,14-prostaglandin J2 (15dPGJ2),8,9 polyunsaturated fatty acids,10 nonsteroidal anti-inflammatory drugs,11 and members of the thiazolinedione family.12
PPAR has been associated with control of inflammation by inhibiting cytokine stimulation of COX-2 and inducible nitric oxide synthase (iNOS) expression in different cell types,13–15 decreasing release of proinflammatory cytokines16 and inhibiting vascular smooth cell migration.17–19 PPAR has also been shown to have antineoplastic and antigrowth properties.18 However, the precise mechanisms defining these effects are unknown.
We recently found that in neonatal ventricular myocytes (NVM), induction of cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase (PGES) by the proinflammatory cytokine interleukin-1ß (IL-1ß) results in preferential production of PGE2.20 In addition, we found that PGE2 induces growth in NVM, suggesting that it plays a detrimental role in the heart. Also, it is known that iNOS is induced on stimulation with IL-1ß21 and that it contributes to myocyte damage after infarction in the rat22 and mouse.23 Thus, we hypothesized that PPAR would exert an anti-inflammatory effect in NVM, decreasing COX-2 and PGES expression and leading to decreased production of the hypertrophic prostanoid PGE2, as well as decreasing iNOS.
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Methods |
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Cell Culture
Primary cultures of NVM were derived from digestion of 1- to 2-day-old neonatal Sprague-Dawley rat hearts (Charles River).24 This protocol was approved by the Henry Ford Hospital IACUC. Myocytes were plated at a density of 1x105/cm2 (1x106 cells per well of a 6-well dish or 5.8x106 cells/10-cm dish) in DMEM (Gibco-BRL) plus 10% FBS (Gibco) and 0.1 mmol/L bromo- deoxyuridine for 40 hours. Serum-free medium supplemented with glutamine, insulin, selenium, and transferrin (SF-DMEM) was then added for 24 hours. Unless otherwise specified, all treatments lasted 24 hours. Cells were pretreated for 1 hour with 15dPGJ2, troglitazone, and GW9662 before treatment with 5 ng/mL IL-1ß.
Isolation of Protein and Western Blot of COX-2, PGES, and iNOS
Protein was isolated from NVM through the use of lysis buffer and protease inhibitors.21 Lysate protein (50 µg per lane) was separated out by electrophoresis on an 8% SDS polyacrylamide gel (for COX-2 and iNOS detection) and transferred to an Immobilon-P PVDF membrane (Millipore); 72-kDa COX-2 and 130-kDa iNOS proteins were detected as described previously.25,26 Microsome-enriched preparations were used for Western blot of PGES. For this, 5.8x106 cells/10-cm dish were washed twice with PBS and scraped from the plate in the same solution. Cells were then centrifuged at 16 000g for 5 minutes, and the pellet was resuspended in a solution composed of 60 mmol/L PIPES, 25 mmol/L HEPES, 0.75% Triton-X 100, 10 mmol/L EGTA, 2 mmol/L MgCl2, 10 µg/mL leupeptin, 5 µg/mL aprotinin, 1 µg/mL pepstatin, 156 µg/mL benzamidine, 1 mmol/L iodoacetamidine, and 0.5 mmol/L PMSF (pH 7.4). After 15 minutes of incubation on ice, the homogenate was placed on top of a 6% sucrose cushion and ultracentrifuged at 230 000g with the use of a Beckman ultracentrifuge and a 70.1-Ti rotor for 40 minutes. The pellet was resuspended in lysis buffer containing protease inhibitors. The 17-kDa PGE2 synthase protein was separated out on a 15% SDS polyacrylamide gel and detected with an anti-rabbit polyclonal antibody (Cayman) diluted 1:500. The appropriate secondary antibody linked to horseradish peroxidase was used for chemiluminescent detection with ECL Western blot reagents (Amersham Pharmacia Biotech). The signal was detected by exposure to Fuji RX film, quantified by laser densitometry, and expressed as optical density (OD) units.
Enzyme Immunoassay for Measurement of PGE2, PGF2, and the Stable PGI2 Metabolite 6-Keto PGF1
1x106 cells per well of a 6-well plate were treated with vehicle, IL-1ß, 15dPGJ2, or 15dPGJ2+IL-1ß in 1 mL SF-DMEM. A 1-mL aliquot of medium from each well was dried down and resuspended in 0.15 mL ultrapure H2O. Aliquots were diluted if necessary and assayed for specific prostaglandins with the use of EIA kits from Cayman. Values from triplicate wells were averaged, and mean±SEM values are expressed as nanograms per milligram of protein.
Isolation of RNA and RT-PCR of COX-2 and PGES
Total RNA was isolated from control and IL-1ß–treated NVM by means of Tri Reagent (MRC), according to the manufacturer’s instructions; 2 µg total RNA was reverse-transcribed in a total volume of 25 µL, using 1 µg random primer (Gibco/BRL) and 200 U MMLV reverse transcriptase (Promega). Five-microliter aliquots of the resulting cDNA were subjected to PCR in a 50-µL reaction volume for amplification of COX-2 (462 bp), PGES (473 bp), and GAPDH (554 bp). Oligonucleotide primers (5'-3') for rat COX-2 were AGT ACG AAG ACC CTG CCT ACG (sense) and TAA GTT GGT GGG CTG TCA AT (antisense). Primers for the complete PGES cDNA were ATG ACT TCC CTG GGT TTG GTG (sense) and TCA GCT GCT GGT CAC AGA TGG (antisense). Primers for rat GAPDH were AAT GCA TCC TGC ACC ACC TGC (sense) and GGA GGC CAT GTA GGC CAT GAG GTC (antisense). A PTC-100 thermal controller (MJ Research) was used for amplification, and the program settings were denaturation for 30 seconds at 95°C, annealing for 60 seconds at 55°C for COX-2, and 60°C for PGES and GAPDH, and extension for 90 seconds at 72°C for 35 (COX-2 and PGES) or 25 cycles (GAPDH). PCR products were separated out on a 2% agarose gel, stained with ethidium bromide, and photographed. Densitometry was used for quantification. COX-2 and PGES were normalized to GAPDH.
Transient Transfection and Luciferase Assay
Transfection was performed by electroporation, and luciferase activity was assayed as described previously27,28;1 µg PPRE-TK-luciferase [containing 3 copies of PPRE, coupled to a minimal thymidine kinase (TK) promoter, kindly provided by Dr Ronald Evans, Salk Institute] was transfected per 3x106 NVM, and the cells were aliquoted into 3 wells of a 12-well plate. After 40 hours, the medium was changed to SF-DMEM, and 24 hours later the cells were treated with 15dPGJ2. After a 24-hour treatment period, NVM were lysed and assayed for luciferase activity using Promega reagents in an OptoComp 1 luminometer. Relative light units (RLU) from triplicate wells were averaged. RLU values in control (untreated) lysates were normalized, and the values of 15dPGJ2-treated lysates were compared with control to give the fold increase. Data are expressed as mean±SEM.
Chemicals
15dPGJ2, GW9662, PGES antibody, and EIA kits for PGE2, PGF2, and 6-keto PGF1 were obtained from Cayman. Troglitazone was obtained from Biomol. PPAR1, COX-2, and iNOS antibodies were obtained from Santa Cruz, and IL-1ß was from Collaborative Biomedical Products.
Statistics
Values are represented as mean±SEM. Differences in mean values were analyzed by Student t test or 1-way ANOVA, with pairwise multiple comparisons made by the Student-Newman-Keuls method. A value of P<0.05 was considered significant.
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Results |
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Detection and Activation of PPAR
in NVMTo determine whether PPAR
receptors are present in NVM, protein from cell lysates was analyzed by Western blot. PPAR1 was detected as a 52-kDa protein (Figure 1A). We next tested whether endogenous PPAR is transcriptionally active in cardiac myocytes. For this, NVM were transiently transfected with the PPRE-TK-luciferase reporter plasmid and treated with the PPAR agonist 15dPGJ2. Figure 1B shows that 15dPGJ2 increased luciferase activity 12.0±2.2-fold compared with untreated NVM. Finally, we cotransfected NVM with the PPRE-TK-Luc reporter gene and dominant negative PPAR cDNA (dnPPAR). As shown in Figure 1B, 15dPGJ2 activation of the PPRE-TK-Luc reporter gene was significantly decreased.
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Effect of 15dPGJ2 on IL-1ß Stimulation of COX-2, PGES, and Prostaglandin Production
High PGE2 resulting from induction of COX-2 participates in inflammation. We tested whether PPAR activation is anti-inflammatory by examining the effect of the natural PPAR agonist 15dPGJ2 on PGE2 production and COX-2 mRNA. 15dPGJ2 reduced IL-1ß–stimulated PGE2 release by 73% (Figure 2A); however, IL-1ß–induced PGF2 and PGI2 levels were not affected (data not shown). In addition, 15dPGJ2 decreased IL-1ß–induced COX-2 mRNA levels by 40% (Figure 2B). IL-1ß induction of COX-2 protein (72 kDa) was similarly inhibited (data not shown).
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Since PGE2 production was inhibited to a greater extent than COX-2 mRNA, we tested whether 15dPGJ2 was affecting the inducible form of PGE2 synthase (mPGES). Figure 3A shows that 15dPGJ2 completely inhibited IL-1ß induction of PGES mRNA. Western blots of microsome-enriched preparations revealed that 15dPGJ2 also blocked IL-1ß induction of PGES protein in NVM (Figure 3B).
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Effect of the PPAR Agonist Troglitazone on COX-2 and PGE2
We used a second PPAR agonist, troglitazone (TRO, 100 µmol/L) to verify our findings with 15dPGJ2. TRO transactivated the PPRE-TK-LUC reporter plasmid (data not shown). TRO also blocked IL-1ß–induced COX-2 (Figure 4A) and PGE2 production (Figure 4B).
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Effect of a PPAR Antagonist, GW9662, on COX-2 and PGES
To further verify that the effects of 15dPGJ2 are PPAR-dependent, we studied the effect of the PPAR antagonist GW9662 (GW, 2 µmol/L). GW blocked the effects of 15dPGJ2 on IL-1ß–induced COX-2 (Figure 5A) and PGES mRNA (Figure 5B). GW alone did not modify either COX-2 or PGES mRNA (data not shown).
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Effect of the PPAR Activator 15dPGJ2 on iNOS
We have previously shown that IL-1ß induces iNOS expression and nitrite production in NVM.25 Since iNOS has been implicated in inflammation, we examined the effect of 15dPGJ2 on IL-1ß induction of iNOS in NVM. Although treatment of NVM with IL-1ß significantly increased iNOS protein, cotreatment with IL-1ß and 15dPGJ2 inhibited iNOS expression (Figure 6A). Troglitazone mimicked the effect of 15dPGJ2 on IL-1ß–induced iNOS expression (Figure 6B). GW was able to partially reverse the inhibitory effect of 15dPGJ2 on IL-1ß–induced iNOS protein (Figure 6C).
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Discussion |
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We found that PPAR
is present and functional in cardiac myocytes. We also demonstrated that its natural agonist 15dPGJ2 exerts anti-inflammatory effects by modulating IL-1ß–stimulated COX-2, PGES, and iNOS in a PPAR-dependent manner.
The PGD2 dehydration product 15dPGJ2 is the most potent endogenous ligand for PPAR yet discovered.8,9 Recently, 15dPGJ2 production was measured in tryptase-stimulated mast cells in culture29 as well as human breast tissue.30 Moreover, prostaglandin D synthase (PGDS) mRNA is expressed in the heart.31 Thus, locally produced PGD2 may result in 15dPGJ2 in myocytes or surrounding cells. Although it is not known whether 15dPGJ2 is produced in myocytes and has autocrine effects to activate PPAR, it is known that the 15dPGJ2 precursor 12-PGJ2 is transported into cells and accumulates in the nucleus.32
We found that 15dPGJ2 decreased IL-ß induction of COX-2 mRNA. This inhibition probably occurred at the transcriptional level. The anti-inflammatory effects of PPAR are thought to be mediated by antagonizing transcription factors such as NF-
B, AP-1, STAT,2 and NFAT,33 some of which are necessary for COX-2 transcription. In fact, Subbaramaiah et al13 showed that stimulation of a breast epithelial cell line with phorbol ester induced COX-2 and that two different PPAR agonists interfered with AP-1–dependent activation of the COX-2 promoter. A PPAR agonist also inhibited IL-ß–induced COX-2 expression in mesangial cells, although the authors suggested that the effects seen are PPAR-independent.34
Previous studies have demonstrated that COX-2 and microsomal PGES are colocalized in the perinuclear envelope, suggesting coordinated biosynthetic activity between enzymes.35 In fact, induction of both COX-2 and PGES results in high level PGE2 production by cardiac myocytes.36 Our data show that 15dPGJ2 blocked IL-1ß stimulation of PGE2 production but did not modify IL-1ß stimulation of PGI2 or PGF2, indicating that PPAR ligand effects are specific for PGES. Naraba et al37 reported that the mouse PGES gene contains several cis-acting elements including C/EBP, AP-1, C/EBPß, and CACCC-binding factor. In contrast to COX-2, no binding sites for NF-B or CREB were found in the PGES promoter region. This may indicate that the mechanisms for PPAR regulation of COX-2 and PGES are distinct. In the same report, the authors showed that induction of PGES is exclusively regulated by the transcription factor early growth response-1 (Egr-1), which can be rapidly and transiently upregulated by various growth factors including IL-1ß.37,38 Also, Egr-1 interacts with CBP/p300 to modulate gene transcription.39 Interestingly, ligand-induced transactivation of PPAR is achieved by receptor recruitment of the coactivator CBP/p300.40 Hence, we speculate that PPAR-mediated inhibition of PGES could result from competition for limited amounts of CBP/p300.
It has been shown that the PPAR ligand 15dPGJ2 exerts anti-inflammatory functions independent of PPAR activation.41 Some of the independent effects of 15dPGJ2 have been attributed to an electrophilic carbon that can react with nucleophils.40 To validate our results, we tested a different PPAR agonist. Troglitazone, an antidiabetic drug belonging to the thiazolinedione family, mimicked the effect of 15dPGJ2 on IL-1ß–induced COX-2, iNOS, and PGE2 production. We found that troglitazone was more effective than 15dPGJ2 in inhibiting IL-1ß induction of COX-2. This may result from the fact that these two selective PPAR agonists bind PPAR and alter its structure in specific ways, resulting in distinct PPAR-coactivator interactions.42 It is also possible that 15dPGJ2 and troglitazone may differ in their stability and affinity binding constant for PPAR in NVM.
Recently, a PPAR-selective antagonist, GW9662, was identified.43 GW9662 has been demonstrated to covalently modify PPAR in a selective and irreversible manner and was found to block the effects of 15dPGJ2 in bone marrow,44 hepatocytes,45 and human smooth muscle cells.46 By using this PPAR-specific antagonist, we demonstrated that the effects of 15dPGJ2 on IL-1ß–induced COX-2 and PGES are essentially mediated by PPAR.
As expected, activation of PPAR inhibited IL-1ß stimulation of the proinflammatory gene iNOS. Previous reports demonstrated that 15dPGJ2 inhibited IL-1ß regulation of iNOS by blocking NF-B activation.47 A similar mechanism is probably responsible for regulation of iNOS in cardiac myocytes in our studies, since we know that IL-1ß activates NF-B in cardiac myocytes, and 15dPGJ2 can partially abrogate this effect (Mendez and LaPointe, unpublished data). However, PPAR-independent effects have been reported.40,48 Our results show that GW only partly reverses the effect of 15dPGJ2 on IL-induced iNOS protein. Thus, we cannot rule out the possibility of some PPAR-independent effect of the natural ligand 15dPGJ2 on iNOS regulation. At this time, we know of no studies that definitively address the PPAR-independent mechanisms that regulate iNOS expression in cardiac myocytes.
iNOS and inducible COX-2 have been implicated in pathophysiological events in the heart.22,49,50 We reported that PGE2 is produced by COX-2 in cardiac myocytes and fibroblasts and that PGE2 analogues stimulate myocyte hypertrophy20 and fibroblast proliferation in vitro (Mendez and LaPointe, unpublished observations). In addition, COX-2 inhibition reduces hypertrophy and fibrosis in vivo in a mouse model of myocardial infarction (LaPointe, unpublished data). PPAR inhibitors have been shown to reduce protein synthesis in myocytes51,52 and vascular smooth muscle cell proliferation.18 It is interesting to speculate that 15dPGJ2 exerts its antigrowth effects in NVM by blocking the release of the hypertrophic prostaglandin PGE2.
Perspectives
PPAR has been shown to participate in cell growth, differentiation, and inhibition of inflammatory responses in multiple cell types important to cardiovascular function, such as vascular smooth muscle cells and cardiac myocytes. In this study, we provide compelling evidence that PPAR activation blunts the release of the hypertrophic and proinflammatory prostanoid PGE2, along with blockade of the inflammatory genes COX-2 and PGES, in a PPAR-dependent manner. In addition, blockade of iNOS is both PPAR-dependent and PPAR-independent. Knowledge of key components of the transcriptional regulation of inflammatory genes by PPAR may provide a viable therapeutic target in the control of cardiac diseases resulting from inflammatory stimuli.
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Acknowledgments |
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This work was supported by National Institutes of Health grant P01-HL-28982 (M.C.L.) and American Heart Association Midwest Affiliate Postdoctoral Fellowship D11533 (M.M.).
Received May 5, 2003; first decision June 2, 2003; accepted June 26, 2003.
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