(Hypertension. 1998;31:218.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Phospholipase A2 Metabolites Regulate Inducible Nitric Oxide Synthase in Myocytes
From the Hypertension and Vascular Research Division (M.C.L., J.R.S.), Henry Ford Hospital, Detroit, Mich.
Correspondence to Dr Margot C. LaPointe, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689. E-mail mclapointe{at}aol.com
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Abstract |
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The proinflammatory cytokine interleukin-1ß (IL) stimulates inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) production in neonatal ventricular myocytes (NVM). In other types of cells, IL also activates phospholipase A2 (PLA2), which liberates arachidonic acid for the pathways involved in eicosanoid production, and induces the cyclooxygenase-2 (COX-2) isoform, which increases prostanoid production. Since NO has been shown to directly stimulate COX activity and the resulting prostanoids to modulate IL induction of iNOS, we questioned whether PLA2 and/or COX products are involved in IL regulation of iNOS and NO production in NVM. We first found that IL induced COX-2 mRNA and protein, resulting in
200-fold and 15-fold increases in PGE2 and 6-keto-PGF1
(the stable metabolite of PGI2), respectively. IL-stimulated prostanoid production was inhibited by the COX-2-specific inhibitor NS-398, as well as the nonspecific COX inhibitor indomethacin (INDO). We next studied the involvement of the PLA2 inhibitor ONO-RS-082 (ONO) and the COX inhibitor INDO in IL regulation of iNOS. Pretreatment with ONO blocked IL-stimulated NO production and iNOS protein, suggesting that PLA2 products are involved in regulation of iNOS synthesis. Unlike ONO, the COX inhibitor INDO had little effect on IL-stimulated NO. In addition to the COX pathway, arachidonic acid (AA) is also metabolized by the lipoxygenase (LO) pathway. The LO inhibitor nordihydroguaiaretic acid (NDGA) decreased IL-stimulated NO and iNOS synthesis. These data suggest that: (1) IL upregulates COX-2 expression and prostanoid production in NVM; and (2) AA metabolites other than COX products, possibly products of the LO pathway, are involved in IL regulation of iNOS.
Key Words: cardiac myocytes • cyclooxygenase • arachidonic acid • lipoxygenase
Abbreviations: AA = arachidonic acid • BAIC = baicalein • COX = cyclooxygenase • DMEM = Dulbecco’s modified Eagle medium • IL = interleukin-1ß • INDO = indomethacin • iNOS = inducible nitric oxide synthase • JNK = c-Jun kinase • LO = lipoxygenase • LPA = lysophosphatidic acid • LPC = lysophosphatidylcholine • MAFP = methyl arachidonyl fluorophosphonate • MAPK = mitogen-activated protein kinase • NO = nitric oxide • NDGA = nordihydroguaiaretic acid • NOx = nitrite • NS-398 = COX-2 inhibitor • NVM = neonatal ventricular myocytes • PAF = platelet-activating factor • PKC = protein kinase C • PLA2 = phospholipase A2
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Introduction |
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We and others have previously shown that the cytokine interleukin-1ß (IL) and endotoxin (bacterial lipopolysaccharide) stimulate inducible nitric oxide synthase (iNOS) mRNA, protein and nitric oxide (NO) production in cardiac myocytes.1–4 iNOS is also upregulated in the heart following infarction, during the development of heart failure, and in inflammatory diseases such as allograft rejection, contributing to cardiac dysfunction.5–8
In addition to iNOS, IL stimulates the expression of a number of other gene products including the inducible cyclooxygenase (COX) isoform, COX-2 (also known as prostaglandin synthase-2 or prostaglandin-endoperoxide synthase-2), and the type II secretory form of phospholipase A2 (sPLA2) (reviewed in 9,10). Stimulation of sPLA2 activity and/or expression can result in enhanced generation of arachidonic acid (AA), which is an important substrate for COX isoforms, lipoxygenases (LO), which are involved in the production of hydroxyeicosatetraenoic acids (HETES) and leukotrienes, and p450 monooxygenases, which are involved in the formation of dihydroxy acids and epoxyeicosatrienoic acids. Induction of COX-2 results in overproduction of prostanoids, including prostaglandins (PGE2, PGI2, and PGF2) and thromboxane. The eicosanoids produced by these three pathways are involved in the regulation of vascular tone and smooth muscle cell growth, platelet aggregation, and inflammation.11,12 While COX-2 and PLA2 have been implicated in a number of inflammatory diseases, such as osteo- and rheumatoid arthritis,9 a pathophysiological role for COX-2 induction in the heart has not been described to our knowledge. In contrast, some studies have shown that inhibition of PLA2 protects the ischemic or ischemic/reperfused heart from injury.13,14 Thus, the role of cytokine-inducible COX-2 and PLA2 in cardiac dysfunction could prove to be of interest.
Both iNOS and COX-2 are stimulated following cytokine treatment of many different types of cells, and, in many cases, NO has been implicated in the activation of COX and PGE2 synthesis.15–19 In contrast, studies with COX inhibitors indicate that prostanoids either have no effect on cytokine induction of iNOS,15,20,21 stimulate it,16 or inhibit it.19 Since IL induces iNOS and since studies have implicated iNOS in the pathophysiology of several cardiac diseases, we questioned (1) whether IL also induces COX-2 in NVM and (2) whether COX products or other PLA2 metabolites are involved in the regulation of iNOS. Our findings indicate that COX-2 is greatly induced in NVM and that PLA2 metabolites, possibly LO products, are involved in IL regulation of iNOS.
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Methods |
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Cell Culture
This protocol was approved by the Henry Ford Hospital Committee for Care and Use of Experimental Animals. Hearts from 1- to 2-day-old neonatal Sprague-Dawley rats (Charles River, Kalamazoo, MI) were minced and digested with trypsin and DNAse to prepare primary cultures of ventricular myocytes as described previously.22 Cells were plated at a density of 1x105/cm2 (1x106 cells/well of a 6-well dish or 5.8x106 cells/10-cm dish) in Dulbecco’s modified Eagle medium (DMEM; Gibco) plus 10% fetal bovine serum (HyClone). Medium lacking serum but supplemented with insulin, transferrin, and selenium was added 24 hours prior to addition of test compounds. Unless otherwise specified, all treatments lasted 24 hours. PLA2, COX, and LO inhibitors were added 1 hour prior to treatment with IL. A range of concentrations for all inhibitors was tested for efficacy and possible cell toxicity. Results show only the effect of 1 or 2 of the concentrations tested.
NO Production
Nitrite (NOx) production, an index of NO production, was measured in media samples by the Griess reaction.23 Values (nmol/mL) from triplicate wells were averaged for each experiment. In most of the experiments, controls (untreated cells) were assigned a value of 1, and values for all treatments were normalized to 1 (fold increase versus control). Data were expressed as mean±SE. Differences in mean values among treatment groups were analyzed by Student’s t-test or one-way analysis of variance with pairwise multiple comparisons made by the Student-Newman-Keuls method. P<.05 was considered significant.
Isolation of RNA and Northern Blot
Total RNA was isolated from NVM and analyzed for 4.2-kilobase (kb) iNOS mRNA and 1.6-kb GAPDH mRNAs. GAPDH mRNA was used to correct for variation in loading of samples onto gels as described previously.4 Electrophoresis, blotting, preparation of radiolabeled cDNA probes, hybridization, and washing of blots were described previously.3 A 1.8-kb ovine cDNA (Biomol) was used to detect the 4.2-kb COX-2 mRNA. Hybridization and washing conditions were identical to those used for iNOS. mRNA levels were quantified by laser densitometry and corrected to GAPDH mRNA.
Isolation of Protein and Western Blot
Protein was isolated from NVM using buffers and protease inhibitors as described previously.4 Lysate protein (50 µg per lane) was separated out by electrophoresis on an 8% SDS-polyacrylamide gel and then transferred to an Immobilon-P PVDF membrane (Millipore). Detection of the 130-kilodalton (kD) iNOS protein was identical to our previous report4 except that we used 0.0001 mg/mL polyclonal iNOS antibody (SC #650; Santa Cruz) and developed the blot with a chemiluminescent kit (ECL, Amersham). To detect the 72-kD COX-2 protein, we used either 0.0001 mg/mL of an anti-goat COX-2 polyclonal antibody (Santa Cruz) or 5 µL/mL of an antirabbit COX-2 polyclonal antibody (Cayman) and the appropriate HRP-conjugated secondary antibody coupled with chemiluminescent detection. The signal was detected by exposure to Fuji RX film and quantified by laser densitometry.
Enzyme Immunoassay for Measurement of PGE2 and the Stable PGI2 Metabolite 6-keto PGF1
Approximately 1x106 cells were cultured in each well of a 6-well plate in 1 mL of serum-free DMEM. Cells were pretreated with PLA2 and COX inhibitors for 1 hour prior to treatment with IL for 24 hours. A 1-mL aliquot of medium from each well was dried down and resuspended in 0.15 mL buffer. Aliquots were diluted anywhere from 1:20 to 1:500 and assayed for PGE2 and 6-keto PGF1 (the stable metabolite of PGI2) using EIA (enzyme immunoassay) kits from Cayman according to the manufacturer’s protocols. According to Cayman, intra- and interassay variability are each 
10%. Data from triplicate wells were averaged and expressed as ng/mL. Differences in mean values among treatment groups were analyzed by one-way ANOVA; pairwise multiple comparisons were made by the Student-Newman-Keuls method. P<.05 was considered significant.
Chemicals
Indomethacin and arachidonic acid were obtained from Sigma; ONO-RS-082, or{2-(amyl-cinnamoyl)amino-4-chlorobenzoic acid, and baicalein from Biomol; and NS-398, NDGA (nordihydroguaiaretic acid) and MAFP (methyl arachidonyl fluorophosphonate) from Cayman. Interleukin-1ß was obtained from Promega. Routine laboratory supplies and chemicals were obtained from Fisher Scientific.
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Results |
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IL Stimulates COX-2 and Prostanoid Production
We have previously shown that IL stimulates NO production in NVM.3,4 Cytokines induce COX-2 in intestinal myofibroblasts,24 chondrocytes,25 rat mesangial cells,26,27 and numerous other types of cells, resulting in enhanced prostanoid production, usually PGE2.9 Thus, we tested for COX-2 upregulation in NVM. Treatment of NVM with 5 ng/mL IL for 24 hours induced COX-2 mRNA (Fig 1A) and protein (Fig 1B). IL stimulated PGE2 production from a control value of 1.02±0.1 ng/mL to 210±28 ng/mL in 24 hours, a 200-fold increase (Fig 1C). In a separate study, we determined the time course of PGE2 production and found that PGE2 did not increase in the medium until between 6 and 24 hours of IL treatment (24-hour control=0.72±0.07 ng/mL; 6-hour IL=1.1±0.4 ng/mL; 24-hour IL=320±64 ng/mL; n=3). We also measured the PGI2 metabolite 6-keto PGF1
. Its production in the same media samples also increased, but less dramatically than PGE2 (control=2.3±0.4 ng/mL; 24-hour IL=33.4±5.6 ng/mL, a 15-fold increase; P<.0001). These data indicate that basal production of PGI2 is greater than PGE2 (2.3±0.4 versus 1.02±0.1 ng/mL; P<.0001), but synthesis of PGE2 is higher in IL-stimulated cells.
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Since IL induces type II sPLA2 mRNA in many types of cells10 and enhanced synthesis of this enzyme can release arachidonic acid (AA), which is a substrate for cyclooxygenase, we postulated that inhibition of sPLA2 activity would prevent IL-stimulated PGE2 production. We found that the PLA2 inhibitor ONO-RS-082 (10 µmol/L) resulted in a greater than 98% decrease in PGE2 production by NVM, suggesting that substrate formation must be stimulated along with cyclooxygenase in order for IL-stimulated prostanoid production (Fig 2A). In addition to several groups of sPLA2, there are two well characterized intracellular PLA2s. Both the Group IV cytosolic PLA2 (cPLA2), which is regulated by Ca++ and phosphorylation and specifically hydrolyzes AA from membrane phospholipids,28 and the Group VI Ca++-independent PLA2 (i PLA2) are inhibited by MAFP.29 However, in contrast to the effect of the sPLA2 inhibitor ONO, MAFP did not inhibit IL-stimulated PGE2 production (control=0.9 0±0.1 ng/mL; IL=207±34 ng/mL; IL+25 µmol/L MAFP=320±52 ng/mL).
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Finally, to distinguish between involvement of COX-1 and COX-2 in IL-stimulated PGE2 production, we tested the effect of a nonspecific COX inhibitor, indomethacin (25 µmol/L), and a COX-2-specific inhibitor, NS-398 (10 µmol/L). Both inhibitors reduced PGE2 production to control values (Fig 2B and 2C).
Involvement of PLA2 Metabolites and/or Cyclooxygenase Products in IL Regulation of iNOS
To find out whether PLA2 metabolites and/or COX products are involved in IL regulation of iNOS, NVM were pretreated with either the sPLA2 inhibitor ONO (5 and 10 µmol/L), the cPLA2 inhibitor MAFP (25 µmol/L), or the COX inhibitor indomethacin (10 and 25 µmol/L) and then stimulated with IL for 24 hours. We found that 10 µmol/L ONO blocked IL-stimulated NO (Fig 3A), and this effect was at the level of iNOS synthesis as IL-stimulated iNOS protein (Fig 3B) was completely inhibited. To exclude nonspecific effects of ONO, four blots were reprobed with reagents to detect COX-2 protein. The data were analyzed by scanning densitometry and indicated that there was no effect of ONO on IL stimulation of COX-2 (IL-stimulated COX-2 protein=1; 10 µmol/L ONO+IL=1.2±0.3; n=4).
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The cPLA2 inhibitor MAFP was less effective in suppressing NO production and iNOS synthesis. IL-stimulated NO production was reduced by 40% (Fig 3C) when NVM were pretreated with 25 µmol/L MAFP, and there was also a small effect on iNOS protein (Fig 3D). Data from 3 Western blots were analyzed by densitometry, and it was found that 10 and 25 µmol/L MAFP reduced IL-stimulated iNOS protein by 20% and 34%, respectively (IL value was arbitrarily set to 1; IL + 10 µmol/L MAFP=0.8±0.1; IL+25 µmol/L MAFP=0.66±0.2).
Since inhibition of sPLA2 by ONO blocked iNOS synthesis as well as reducing prostanoid production to control levels (Fig 2) and since other studies have shown both positive and negative effects of prostanoids on IL regulation of iNOS,16,19 we next tested the effect of COX inhibition on IL regulation of iNOS. We used 25 µmol/L INDO, since this concentration totally inhibited prostanoid production in NVM; however, there was no effect on NO production (Fig 4A), iNOS mRNA (Fig 4B) and protein (Fig 4C). Results using the COX-2 inhibitor NS-398 were similar (data not shown).
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Because inhibition of PLA2 prevented IL stimulation of iNOS, whereas COX inhibition did not, we hypothesized that either AA itself or one of its metabolites, such as a product of the LO pathway, might be involved in IL regulation of iNOS. When AA at 5–250 µmol/L was added to the cell culture medium, it was taken up and metabolized into prostanoids (PGE2 and 6-keto PGF1), but had no effect on NO production on its own (data not shown). Therefore, we tested the involvement of the LO pathway using the inhibitor NDGA. As shown in Fig 5A, 25 µmol/L NDGA inhibited IL-stimulated NO, and this effect was at the level of iNOS synthesis since both iNOS protein (Fig 5B) and mRNA (Fig 5C) were suppressed. To control for potential nonspecific effects of NDGA, a second LO inhibitor, baicalein, was tested for its effect on IL-stimulated iNOS mRNA. Fig 5D shows that 25 µmol/L baicalein also suppressed IL-stimulated iNOS mRNA.
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Discussion |
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Two important findings of our studies are that IL induces COX-2 and PGE2 production in cardiac myocytes, and that a PLA2 metabolite, possibly a product of the LO but not the COX pathway, is involved in IL regulation of iNOS. Inhibition of sPLA2 and LO affects IL stimulation of iNOS at the level of gene expression.
Cytokines, growth factors, phorbol ester, and bacterial endotoxin (LPS) induce COX-2 in many types of cells.9 To our knowledge, our studies represent the first demonstration of IL induction of COX-2 in cardiac myocytes. IL has been shown to regulate COX-2 at the transcriptional level in the pancreas17 and at the post-transcriptional level to increase mRNA stability in chondrocytes25 and rat mesangial cells.30 The AUUUA motif in the 3' untranslated region of the COX-2 mRNA seems to contribute to its instability, and it is a target for binding of stabilizing factors whose activity is regulated by IL.30 IL regulation of COX-2 in myocytes is likely to involve both mechanisms, although we did not address this question directly. We did observe variable but small amounts of COX-2 mRNA and protein in untreated myocytes, which suggests that it is continuously present at low levels, and these levels were increased at least 10-fold by IL. The presence of COX-2 in untreated myocytes was not the result of LPS contamination of our cell culture system, since we did not observe iNOS mRNA or protein in these control samples.
Induction of COX-2 resulted in 200-fold and 15-fold increases in PGE2 and PGI2, respectively, such that PGE2 became the dominant IL-stimulated prostanoid, as described for other types of cells as well.9 Studies with the specific inhibitor NS-398, as well as the large increases in COX-2 mRNA and protein, would seem to indicate that COX-2 was responsible for much of the enhanced prostanoid production. However, we cannot exclude an effect of NS-398 on PGE2 production by COX-1, since Panara et al have shown that 10 µmol/L NS-398 inhibits thromboxane B2 synthesis (primarily a COX-1 product) by 50% in human whole blood.31 We also found that PGI2 was the major prostanoid secreted by control NVM, which is consistent with the recent study by Oudot et al.32 They found that PGI2 was the major prostanoid secreted into the medium, followed by PGE2, PGF2, and thromboxane B2, and that the profile of prostanoid production changed during hypoxia (increase in PGE2) and reoxygenation (increase in PGI2),32 reflecting in vivo studies of ischemic/ reperfused hearts.33
Our data indicate that upregulation and/or activation of type II sPLA2 are necessary for enhanced eicosanoid production in IL-stimulated NVM. The substrate for eicosanoid production is AA liberated by hydrolysis of the sn-2 fatty acyl bond of membrane phospholipids (primarily phosphatidylcholine, -serine, -inositol and -ethanolamine) by PLA2. This process also results in the liberation of lysophospholipids, which themselves are effector molecules. There are several groups of PLA2s, which differ in localization, regulation, and function. Two groups seem to be able to release AA from phospholipids, IIA sPLA2 and IV cPLA2.34 cPLA2 is generally considered to be more selective for releasing AA from phospholipids and thus contributing to eicosanoid synthesis in many types of cells.35 However, in our studies, the sPLA2 inhibitor ONO totally eliminated IL induction of PGE2 in NVM, but the cPLA2/iPLA2 inhibitor MAFP did not, suggesting that sPLA2 is the major AA-liberating enzyme in IL-treated cardiac myocytes. IL has been shown to induce type II sPLA2 in mesangial cells, chondrocytes, hepatoma, and macrophages,36–39 which occurs at the level of gene expression and requires several hours of stimulation. In contrast, IL and other growth factors rapidly activate cPLA2.38 Thus, although we did not measure sPLA2 mRNA or AA release, our data, based on our inhibitor and time course studies and indicating that PGE2 does not appear in the cell culture medium of cells until 6 to 24 hours after IL treatment, point to IL induction of sPLA2.
Previous studies have shown that prostanoids can modulate cytokine regulation of iNOS in different types of cells.15,16,19–21 Our studies are the first to show that PLA2 metabolites, but not cyclooxygenase products, may be involved in IL regulation of iNOS. These results suggest that IL regulation of iNOS in cardiac myocytes is mediated or modulated by (1) AA itself, (2) lysophospholipid products or derivatives (lysophosphatidylcholine, LPC; platelet-activating factor, PAF; and lysophosphatidic acid, LPA), or (3) an eicosanoid product(s) of the LO and/or p450 monoxygenase pathways. Although AA has been shown to modulate signaling pathways and activate transcription factors,40–43 it was not able to stimulate NO production or induce iNOS in cardiac myocytes. While we cannot absolutely exclude lysophospholipid products as a factor in IL regulation of iNOS, we have indirect evidence that they are not. PAF, LPA and LPC actions are mediated by phospholipase C and protein kinase C (PKC).44,45 Our previous work indicates that PKC inhibition by staurosporine does not block IL stimulation of NO in cardiac myocytes,3 and thus we do not believe these agents are major mediators of IL regulation of iNOS. In contrast, our data would suggest that an eicosanoid product is most likely responsible. Preliminary studies with the p450 monooxygenase inhibitors 17-ODYA and ketoconozole seem to eliminate this pathway as a mediator/modulator of IL regulation of iNOS, but additional experiments are required to confirm this (M.C.L. and J.R.S., unpublished observations). In contrast, the LO inhibitor NDGA reduced IL-stimulated iNOS mRNA, protein and NO production, demonstrating the importance of this pathway in the regulation of iNOS gene expression.
Studies have suggested that NDGA has a number of non-specific effects, including inhibition of mitochondrial respiration and antioxidant properties.46 If NDGA is acting as an antioxidant, its mechanism of action is completely different from that of the antioxidant n-acetylcysteine, which we have found has no effect on IL stimulation of iNOS synthesis in cardiac myocytes.47 Moreover, we have tested the effect of a second LO inhibitor, baicalein, and found that it also inhibits iNOS mRNA.
Our studies have not identified the major LO product (5-, 12-, 15-HETE or leukotrienes generated by 5-, 12-, and 15-lipoxygenase) and the mechanism by which this product mediates/modulates IL regulation of iNOS. LO products have been implicated in stimulation of mitogen-activated protein kinase (MAPK) and c-Jun kinase (JNK) signaling cascades,43,48 induction of c-fos and c-jun mRNA49 and activation of transcription factors such as AP-149 and NF
B.50,51 We have shown previously that a tyrosine kinase signaling cascade is required for IL induction of iNOS,4 and that IL activates NFB in cardiac myocytes,52 but only NFB has been implicated in the transcriptional regulation of iNOS.53 Of interest, a tyrosine kinase signaling pathway activates both cPLA235 and 5-LO,54 causing both to translocate to the nuclear membrane,54 where they may play a novel role in transcriptional regulation of genes involved in the inflammatory response. Future studies will determine whether IL stimulation of a LO product results in activation of the MAPK pathway and directly regulates NFB and/or other nuclear effectors.
In conclusion, the proinflammatory cytokine IL induces a wide array of inflammatory mediators in cardiac myocytes, including iNOS, AA and other sPLA2 metabolites, COX-2 protein and prostanoids, and LO products. One of the novel results reported here is that COX-2 is a major protein stimulated by IL in cardiac myocytes, resulting in a 200-fold increase in PGE2. Moreover, it would appear that IL also induces LO products that are able to mediate/modulate IL regulation of iNOS, a process heretofore not reported for iNOS. The excessive production of NO and eicosanoids by IL-stimulated myocytes, coupled with crosstalk between the NO-forming and eicosanoid-forming pathways, may contribute to myocyte dysfunction and tissue injury in cardiac pathologies involving the inflammatory response, such as infarction and heart failure.
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Acknowledgments |
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This work was supported by NIH grants HL 03188 and 28982 to MCL. The authors thank Kim Saracino for her excellent technical assistance.
Received September 16, 1997; first decision October 16, 1997; accepted October 29, 1997.
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