(Hypertension. 2000;35:249.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Role of Ca2+-Independent Phospholipase A2 in the Regulation of Inducible Nitric Oxide Synthase in Cardiac Myocytes
From the Hypertension and Vascular Research Division, 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. E-mail mclapointe{at}aol.com
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Abstract |
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Abstract—We have previously shown that the regulation by interleukin-1ß (IL-1ß) of inducible nitric oxide synthase (iNOS) involves phospholipase A2 (PLA2) metabolites in neonatal ventricular myocytes. Based on studies in which ONO-RS-082 is used to inhibit secretory PLA2 and methyl arachidonyl fluorophosphonate is used to inhibit cytosolic PLA2, our data suggest that a secretory PLA2 metabolite was involved in the regulation by IL-1ß of iNOS. In addition, a third PLA2 isoform, which is Ca2+ independent (iPLA2), has also been detected in cardiac myocytes and shown to be regulated by cytokines. We tested whether iPLA2 metabolites are involved in the regulation by IL-1ß of iNOS with the use of bromoenol lactone (BEL), a specific and irreversible inhibitor of iPLA2. For this, we measured IL-1ß–stimulated nitrite (NOx) production with use of the Griess reagent, prostaglandin E2 (PGE2) production with use of an enzyme immunoassay, and arachidonic acid release in the presence and absence of BEL. We also detected iNOS and iPLA2 proteins by Western blotting. Treatment with IL-1ß (5 ng/mL) for 24 hours stimulated NOx production by 8-fold and iNOS protein levels by at least 10-fold. In addition, arachidonic acid release was increased by 1.6-fold and PGE2 production was increased by 300-fold. When neonatal ventricular myocytes were treated with 10 µmol/L BEL, both IL-1ß–stimulated PGE2 production and arachidonic acid release were inhibited. BEL inhibited IL-1ß–stimulated NOx production and iNOS protein by 88% and 93%, respectively. Lysophosphatidic acid, but not arachidonic acid or lysophosphatidylcholine, stimulated iNOS expression. Our results indicate that an iPLA2 metabolite, perhaps lysophosphatidic acid, may be involved in the IL-1ß–signaling pathway, regulating the synthesis of iNOS.
Key Words: nitric oxide • arachidonic acids • interleukins • myocytes
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Introduction |
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Much recent research has focused on regulation of the cytokine-inducible nitric oxide (NO) synthase isoform (iNOS). The iNOS isoform produces large quantities of NO over prolonged periods of time. In the cardiovascular system, NO produced by iNOS is a major pathophysiological mediator of septic shock: it has been shown to mediate the negative inotropic effects of cytokines, it plays a role in myocardial cell death after ischemia, and it may be a factor in the development of heart failure.1 2 3 4 5 6 7 8
Proinflammatory cytokines are released locally in a variety of conditions associated with myocardial inflammation, including cardiac allograft rejection, myocardial infarction, myocarditis, and idiopathic cardiomyopathy.9 10 11 In addition, elevated levels of circulating cytokines have been described in advanced heart failure.12 13 These proinflammatory cytokines are potent inducers of NOS in cardiac myocytes.14 15 16 Interleukin-1ß (IL-1ß) is released primarily by monocytes and macrophages, as well as by nonimmune cells such as fibroblasts and endothelial cells, during injury, infection, invasion, and inflammation17 18 and is a major regulator of iNOS in neonatal15 and adult16 cardiac myocytes.
In addition to iNOS, IL-1ß induces the synthesis or stimulates the activity of a number of mediators of the inflammatory response, including cyclooxygenase-2 (COX-2)19 20 and phospholipase A2 (PLA2) isoforms.21 22 PLA2 acts on membrane phospholipids to release arachidonic acid (AA), which is involved in eicosanoid production by cyclooxygenases, lipoxygenases, and P450 monooxygenases. Other PLA2 metabolites include lysophospholipid products, which may be associated with cytokine-induced inflammation and cell injury.18
Several different PLA2 isoforms have been identified in the heart, including low-molecular-weight secretory PLA2 (sPLA2), high-molecular-weight cytosolic PLA2 (cPLA2), and Ca2+-independent intracellular PLA2 (iPLA2).20 21 22 23 Most PLA2 activity in the mammalian myocardium involves iPLA2, and the 80- and 40-kDa isoforms are the most well characterized.21 24 25 iPLA2 has been shown to play an important rolein (1) signal transduction in response to several agonists, (2) plasma membrane remodeling, and (3) cell injury during myocardial ischemia.21 23 25 In addition, studies suggest that IL-1ß can increase iPLA2 activity in adult ventricular myocytes.22
Prostanoids26 and AA metabolites19 have been shown to modulate IL-1ß induction of iNOS. Previously, we showed that an inhibitor of sPLA2, but not of cPLA2, prevented IL-1ß–stimulated NO production and iNOS synthesis.19 Because of the abundance of iPLA2 in the heart, we extended these studies to determine whether iPLA2 metabolites are involved in the stimulation by IL-1ß of iNOS and NO production. In addition, using the selective iPLA2 inhibitor bromoenol lactone (BEL), we determined whether iPLA2 contributes to AA release and PGE2 production in neonatal ventricular myocytes (NVMs) treated with IL-1ß.
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Chemicals
BEL and rabbit iPLA2 polyclonal antiserum were purchased from Cayman Chemical Co. The iNOS antibody was obtained from Santa Cruz. IL-1ß was obtained from Promega. Protein molecular weight markers, horseradish peroxidase–linked anti-mouse and anti-rabbit secondary antibodies, and enhanced chemiluminescence Western blotting detection reagents were obtained from Amersham. Laboratory supplies and chemicals were obtained from Sigma and Fisher.
Cell Culture
Primary cultures of NVMs were derived from digestion of 1- or 2-day-old neonatal Sprague-Dawley rat hearts as described previously.27 Female Sprague-Dawley rats with pups were obtained from Charles River. The protocol was approved by the Henry Ford Hospital Committee for Care and Use of Experimental Animals. Cells were plated at a high density in DMEM (GIBCO BRL) plus 10% FBS (Hyclone) onto 6-well (1x106 cells/well) or 12-well (0.5x106 cells/well) dishes for 40 hours, after which serum-free medium supplemented with glutamine, insulin, selenium, and transferrin was added for 24 hours before the test compounds were added. Cells were pretreated for 30 minutes with the iPLA2 inhibitor BEL (10 µmol/L) before the addition of IL-1ß for 24 hours.
NO Production
Nitrite (NOx), an index of NO production, was measured in medium samples with use of the Griess reaction. A 1-mL aliquot of medium from each well was dried down and resuspended in 0.15 mL UltraPure water (Cayman). Duplicate 50-µL aliquots were assayed for NOx. Values from triplicate wells (in nmol/mL) were averaged for each experiment. Data are expressed as mean±SEM.
Enzyme Immunoassay for Measurement of PGE2
Aliquots of dried medium previously assayed for NOx were diluted 1:20 to 1:2000 and assayed for prostaglandin E2 (PGE2) with the use of an enzyme immunoassay kit from Cayman according to the manufacturer’s protocol. Data from triplicate wells were averaged and expressed in ng/mL.
Isolation of Protein and Western Blot Analysis
Protein was isolated from ventricular myocytes through the use of buffers and protease inhibitors as described previously.19 28 Lysate protein (50 µg/lane) was separated through electrophoresis onto an 8% SDS–polyacrylamide gel and transferred to an Immobilon-P PVDF membrane (Millipore). For detection of the 130-kDa iNOS protein, we used 0.0001 mg/mL polyclonal iNOS antibody (SC 650; Santa Cruz). A polyclonal antibody (used at 1:1000 dilution) generated against the amino-terminal domain of iPLA2 detected an 80- to 85-kDa protein. The appropriate secondary antibody linked to horseradish peroxidase was used for chemiluminescent detection of the iNOS and iPLA2 proteins. The signal was detected through exposure to Fuji RX film and analyzed with scanning densitometry. In most cases, the densitometry value for IL-1ß–treated cells was assigned a value of 1, and values for all treatments were normalized to 1 (-fold change versus IL-1ß).
Measurement of AA Release
IL-1ß–stimulated AA release from radiolabeled membrane phospholipids was determined through the measurement of [3H]AA in the NVM medium as described previously.22 Briefly, NVMs (0.5x106 cells in 1 mL culture medium) were incubated at 37°C with 3 µCi [3H]AA for 24 hours to label phospholipids in the membranes. This resulted in 
50% incorporation of radiolabeled AA into membrane phospholipids (47±9%; n=7). Labeling medium was removed, and the cells were washed 3 times with serum-free DMEM containing 1% BSA (fatty acid free). After incubation at 37°C for 15 minutes, myocytes were treated with IL-1ß alone or with IL-1ß and BEL for 24 hours. At the end of the treatment period, the medium was removed from the myocyte cultures and centrifuged to remove contaminating cells, and triplicate 100-µL aliquots were counted in 1 mL of scintillation fluid. NVMs were scraped from the wells into 1 mL of serum-free DMEM containing 1% BSA and pelleted, and the pellets were dissolved in 200 µL of 10% SDS. A 100-µL aliquot of the pellet was counted in 1 mL of scintillation fluid with the use of a Packard 3320/3330 TRI-CARB ß-counter. The amount of radioactivity in the medium (M) plus that in the cell pellet (C) represents the total amount of [3H]AA in each sample. AA release was calculated as the amount of radioactivity in the medium divided by total radioactivity: [M/(C+M)x100]. For each experiment, cpm in the control sample was set at 100%, and samples containing IL-1ß and IL-1ß plus BEL were normalized to control.
Statistical Analysis
Values are mean±SEM, with N values representing the number of experiments. Statistical significance was evaluated with Student’s t test or ANOVA with the appropriate correction for multiple comparisons (Newman-Keuls method). P<0.05 was considered significant (compared with control unless otherwise specified).
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Results |
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Effect of the iPLA2 Inhibitor on PGE2 Production and AA Release in IL-1ß–Treated NVMs
We have previously shown that inhibition of sPLA2 with ONO-RS-082 prevents IL-1ß–stimulated PGE2 production but inhibition of cPLA2 with methyl arachidonyl fluorophosphonate (MAFP) does not.19 We questioned whether the BEL-sensitive iPLA2 isoform is also involved in the hydrolysis of membrane phospholipids and the release of AA to form PGE2. For these experiments, we used BEL at a concentration of 10 µmol/L, which is known to significantly inhibit iPLA2.29 Figure 1A shows that the exposure of NVMs to 5 ng/mL (0.3x10-9 mol/L) IL-1ß for 24 hours increased PGE2 production by 300-fold (IL-1ß 275±43 ng/mL, control 0.9±0.05 ng/mL). Pretreatment with 10 µmol/L BEL reduced IL-1ß–stimulated PGE2 production by >99% (BEL/IL-1ß 4.2±1.3 ng/mL). When BEL was added for just 1 to 2 hours instead of being present for the entire IL-1ß treatment period, it still inhibited PGE2 production, which is consistent with its role as an irreversible inhibitor (data not shown).
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To test whether the inhibition of PGE2 production by BEL was due to a decrease in AA release, we next examined the effect of the iPLA2 inhibitor on IL-1ß stimulation of AA release. Figure 1B shows that exposure of cardiac myocytes to IL-1ß for 24 hours resulted in a 1.6-fold increase in AA release. In contrast, pretreatment of NVMs for 30 minutes with 10 µmol/L BEL prevented IL-1ß–stimulated AA release. Thus, the data in Figure 1 suggest that iPLA2 can hydrolyze membrane phospholipids to release AA and form PGE2.
Effect of the iPLA2 Inhibitor on IL-1ß Stimulation of NO Production and iNOS Synthesis
Because the inhibition of iPLA2 by BEL blocked AA release and PGE2 production and because our previous results suggested that AA metabolites are involved in the regulation of iNOS IL-1ß,19 we next tested the effect of iPLA2 inhibition on IL-1ß regulation of iNOS synthesis and NOx production. When ventricular myocytes were pretreated with BEL and then treated with IL-1ß, IL-1ß stimulation of nitrite production was inhibited by 88% (IL-1ß 25.2±0.9 nmol/106 cells, BEL/IL-1ß 3.1±0.3 nmol/106 cells; Figure 2). To test whether the decrease in NO production was the result of a decrease in iNOS synthesis, protein samples from cell lysates were analyzed by Western blotting. BEL decreased IL-1ß–stimulated iNOS by 93% (BEL/IL-1ß 0.07±0.02-fold, IL-1ß 1-fold; Figure 3). To test whether BEL was nonspecifically inhibiting general protein synthesis, we reprobed several blots with an antibody to ß-actin but found no effect. Thus, the induction of iNOS by IL-1ß seems to require metabolites generated by a BEL-sensitive PLA2 isoform.
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Regulation of iNOS by PLA2 Metabolites
Because the inhibition of iPLA2 prevented the stimulation of iNOS by IL-1ß, we hypothesized that either AA itself or other PLA2 metabolites, such as lysophosphatidylcholine (LPC) or lysophosphatidic acid (LPA), might be involved in the regulation of iNOS by IL-1ß. AA alone (25 µmol/L) was unable to stimulate iNOS expression (Figure 4); therefore, we tested the involvement of LPC and LPA (10 µmol/L). LPA alone stimulated iNOS protein by at least 8.4-fold, whereas LPC had no effect (Figure 4). LPA was also able to stimulate iNOS expression in the presence of IL-1ß and BEL (data not shown), suggesting that BEL was not nonspecifically inhibiting critical signaling molecules, like activation of protein kinase C (PKC).25 Thus, the induction of iNOS by IL-1ß seems to involve metabolites generated by iPLA2, such as LPA.
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Effect of IL-1ß on iPLA2 Synthesis
Because IL-1ß is known to stimulate the activity of a Ca2+-independent iPLA2 isoform,22 we used Western blotting to test whether synthesis of the 80- to 85-kDa iPLA2 isoform is regulated by IL-1ß. In contrast to our expectations, IL-1ß decreased iPLA2 protein (IL-1ß 0.46±0.06-fold, control 1-fold; Figure 5).
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Discussion |
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The principal new finding of the present study is that the induction of iNOS by the inflammatory cytokine IL-1ß is mediated by PLA2 metabolites that are generated by a BEL-sensitive iPLA2 isoform in cardiac myocytes. These data extend our previous finding that an AA metabolite, perhaps generated via a lipoxygenase, but not a cyclooxygenase, pathway, is involved in the regulation of iNOS.19 Because IL-1ß induces a number of inflammatory mediators in cardiac myocytes besides NO, including COX-2 products, AA, and PLA2 metabolites, and because all of them can act as signaling molecules, it is not surprising that a number of these products enhance or mediate IL-1ß stimulation of iNOS.
IL-1ß elicits its multiple biological actions via several signal transduction pathways, and its receptor may be coupled to phospholipases, including PLA2.18 PLA2 catalyzes the hydrolysis of fatty acids esterified at the sn-2 position of phospholipids, generating AA. Other products of this reaction include LPA, LPC, and platelet-activating factor. Different isoforms of PLA2 have been identified in a variety of cells. In NVMs, we identified cPLA2 through Western blotting20 and sPLA2 through RT-PCR (E.I. and M.C.L., unpublished observations, 1999). In the present study, we examined the role of a BEL-sensitive Ca2+-independent isoform in the regulation of iNOS and detected an 80- to 85-kDa iPLA2 isoform by Western blotting. We also determined that a BEL-sensitive isoform is important in AA release and PGE2 formation. The iPLA2 isoform has been implicated in AA release by several types of cells22 30 31 ; however, Murakami et al31 produced stable transfectants of sPLA2-, cPLA2-, and iPLA2-overexpressing cells and found that despite the ability of iPLA2 to release AA, it was unable to supply AA for PGE2 generation by COX-2. Our data on BEL suggest that AA released by iPLA2 is metabolized into PGE2 by COX-2. However, an alternative explanation is that an iPLA2 metabolite is involved in IL-1ß–stimulated COX-2 synthesis and that a decrease in COX-2 will result in inhibition of PGE2 formation. In support of this, preliminary data from our laboratory indicate that BEL totally inhibits IL-1ß–stimulated COX-2 (E.I. and M.C.L., unpublished data, 1999). Thus, in NVMs, IL-1ß stimulates the release of AA through a BEL-sensitive PLA2 isoform, but whether AA generated via this mechanism can directly couple to PGE2 formed by COX-2 is unknown.
At least 2 different iPLA2 isoforms exist in cardiac myocytes. Although there is some confusion in the literature regarding the subcellular location of these isoforms, studies indicate that both 80- and 40-kDa iPLA2 isoforms can be either cytosolic or membrane associated.21 22 23 32 33 34 35 McHowat and Liu22 reported that IL-1ß increases the activity of a membrane-associated Ca2+-independent iPLA2 in adult rat ventricular myocytes when plasmenylcholine is used as a substrate and that this BEL-sensitive enzyme releases AA. In a subsequent study, these authors showed that the membrane-associated iPLA2 isoform was 82 kDa.29 Using crude homogenates of NVMs and the same polyclonal antibody, we also detected an 80- to 85-kDa iPLA2 isoform. We found that IL-1ß decreased the level of this iPLA2 isoform, which might argue against its involvement in either AA release or PGE2 production and implicate another isoform in these processes. In support of this, it has been reported that the 80- to 85-kDa isoform is inhibited by both BEL and MAFP and that the 40-kDa form is inhibited by BEL.21 We have previously shown that MAFP, which inhibits cPLA2 and some iPLA2 isoforms, has very little effect on IL-1ß–stimulated PGE2 production.19 Because our present study shows that BEL inhibits AA release and PGE2 production, it is possible that the BEL-sensitive 40-kDa isoform described by Hazen et al,36 or some entirely new isoform, is involved in our system; additional studies will be required to identify the BEL-sensitive isoform found to be active in the present study.
By acting through multiple signaling pathways, IL-1ß regulates iNOS expression. We have previously shown that tyrosine kinases28 and AA metabolites, presumably derived from a lipoxygenase pathway,19 are involved in this regulation. An iPLA2 isoform has been shown to generate the second-messenger lipids LPA and LPC.32 37 38 Here, for the first time, we have implicated the PLA2 metabolite LPA in iNOS regulation. Xu et al39 have shown that phosphatidic acid, but not LPA, induces protein synthesis in adult myocytes and that this process involves the activation of phospholipase C, tyrosine kinase, and PKC. Whether phosphatidic acid also regulates iNOS in NVMs is presently unknown; nevertheless, activation of kinases such as tyrosine kinase and PKC by LPA may mediate the regulation of iNOS by IL-1ß.
With regard to the possible involvement of PLA2 metabolites in the regulation of iNOS by IL-1ß, we have data that indicate both sPLA2 and iPLA2 play roles. There are several possibilities to explain these results. It is possible that BEL and ONO-RS-082, at the concentrations used in these cell culture experiments, inhibit PLA2 activity nonspecifically, but this seems unlikely based on a number of publications.33 40 Balsinde and Dennis40 tested the effect of BEL on PLA2 isoforms in P388D1 macrophages and found that it had no effect on either cPLA2 or sPLA2 activity in cellular homogenates. BEL can reportedly also inhibit the enzyme that converts phosphatidic acid to diacylglycerol (DAG), potentially resulting in decreased DAG levels and inhibition of DAG-sensitive events, such as the activation of PKC.25 To address this issue, we added LPA to IL-1ß– and BEL-treated myocytes and found that LPA could overcome the BEL-induced decrease in iNOS. This indicates that BEL is not causing a generalized inhibition of critical signaling molecules. In addition, it is possible that iPLA2 and sPLA2 are both required for the regulation of iNOS by IL-1ß. iPLA2 and sPLA2 may act in parallel signaling pathways, both of which are necessary for the regulation of iNOS by IL-1ß. Alternately, it is possible that there is cross-talk between sPLA2 and iPLA2 and that iPLA2 is activated first, resulting in the activation or induction of synthesis of sPLA2. If induction or activation of iPLA2 is needed for the action of sPLA2, this would explain why IL-1ß fails to induce iNOS in the presence of BEL. Although we are unaware of any studies indicating cross-talk between sPLA2 and iPLA2, there are numerous studies demonstrating that cPLA2 and sPLA2 interact in cell signaling.31 40 41 42 43
In conclusion, our data suggest that a BEL-sensitive PLA2 isoform releases AA from membrane phospholipids in NVMs and that one of its metabolites, perhaps LPA, mediates the regulation of iNOS and NO production by IL-1ß. We must determine the specific BEL-sensitive PLA2 isoform involved in this process, as well as the signaling mechanisms employed. Because iPLA2 is involved in the release of AA and the subsequent formation of many important secondary messengers and because it plays a role in phospholipid remodeling, an understanding of its role in the regulation of iNOS by IL-1ß may provide some insight into the roles of both proteins in cardiac pathophysiology.
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Acknowledgments |
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This work was supported by NIH grants HL-03188 and HL-28982 (Dr LaPointe). We thank Fangfei Wang for preparation of the neonatal cardiac myocyte cultures.
Received September 13, 1999; first decision October 11, 1999; accepted October 19, 1999.
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C. M. Jenkins, X. Han, D. J. Mancuso, and R. W. Gross Identification of Calcium-independent Phospholipase A2 (iPLA2) beta , and Not iPLA2gamma , as the Mediator of Arginine Vasopressin-induced Arachidonic Acid Release in A-10 Smooth Muscle Cells. ENANTIOSELECTIVE MECHANISM-BASED DISCRIMINATION OF MAMMALIAN iPLA2s J. Biol. Chem., August 30, 2002; 277(36): 32807 - 32814. [Abstract] [Full Text] [PDF]
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N. Degousee, E. Stefanski, T. F. Lindsay, D. A. Ford, R. Shahani, C. A. Andrews, D. J. Thuerauf, C. C. Glembotski, T. J. Nevalainen, J. Tischfield, et al. p38 MAPK Regulates Group IIa Phospholipase A2 Expression in Interleukin-1beta -stimulated Rat Neonatal Cardiomyocytes J. Biol. Chem., November 16, 2001; 276(47): 43842 - 43849. [Abstract] [Full Text] [PDF]
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Z. Ma, S. Ramanadham, M. Wohltmann, A. Bohrer, F.-F. Hsu, and J. Turk Studies of Insulin Secretory Responses and of Arachidonic Acid Incorporation into Phospholipids of Stably Transfected Insulinoma Cells That Overexpress Group VIA Phospholipase A2 (iPLA2beta ) Indicate a Signaling Rather Than a Housekeeping Role for iPLA2beta J. Biol. Chem., April 13, 2001; 276(16): 13198 - 13208. [Abstract] [Full Text] [PDF]
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