© 2000 American Heart Association, Inc.
Vascular Biology |
Endothelin-1 and Smooth Muscle Cells
Induction of Jun Amino-Terminal Kinase Through an Oxygen Radical–Sensitive Mechanism
From Innere Medizin III, Universität Heidelberg, and Deutsches Krebsforschungs Institut (U.S.), Heidelberg, Germany.
Correspondence to Dr Jörg Kreuzer, Universität Heidelberg, Innere Medizin III, Bergheimer Str. 58, 69115 Heidelberg, Germany. E-mail Joerg Kreuzer{at}med.uni-heidelberg.deKreuzer@med.uni-heidelberg.de
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Abstract |
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Abstract—Endothelin-1 (ET-1) has been proposed to contribute to atherogenesis and plaque rupture in coronary heart disease through activation of mitogen-activated protein kinases (MAPKs) in smooth muscle cells (SMCs). Reactive oxygen species (ROS) have been shown to be important signal transduction molecules in SMCs. Thus, the present study aimed to assess the role of ROS in ET-1–mediated activation of c-Jun amino-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK) 1/2. Rat SMCs were exposed to ET-1 over time at concentrations from 10-6 to 10-10 mol/L, and MAPK activity was quantified. Activation of JNK and ERK was observed with a maximum stimulation at 10-7 mol/L ET-1. JNK and ERK were activated by ET-1 binding to a single receptor (ET-1A) but differed in their downstream mechanisms: only JNK activation was sensitive to the radical scavenger N-acetylcysteine and diphenylene iodonium, an inhibitor of NADPH oxidase, indicating a role for ROS. The downstream MAPK effector and proinflammatory transcription factor, the activator protein-1 complex, was maximally activated 2 hours after the addition of ET-1. It was mainly composed of the JNK substrate c-Jun, and activation was also dependent on ROS formation. We suggest that plaque activation by ET-1 can be mediated through ROS. It can be hypothesized that the clinical benefit of antioxidants in the treatment of atherogenesis may partially depend on neutralization of ET-1–mediated ROS production.
Key Words: endothelin-1 • atherosclerosis • reactive oxygen species • mitogen-activated protein kinase • smooth muscle
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Introduction |
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Several lines of evidence suggest a role for endothelin-1 (ET-1) in the pathogenesis of atherosclerosis, including immunohistochemical studies demonstrating an increased accumulation of ET-1 in human atheroma.1 Furthermore, a direct correlation could be shown between the amount of ET-1 present in human coronary artery lesions and unstable angina.2 In animal experiments, endothelin antagonists had a protective effect against atherosclerosis.3 4 A release of endothelin, in vitro, by smooth muscle cells (SMCs) themselves was also demonstrated.5 The proatherogenic properties of endothelin are attributed to its vasoconstrictive action,2 6 7 and more recently, ET-1 has been reported to activate SMCs.8 9 As shown by numerous studies, activation of SMCs can be an important step in the inflammatory response of the vessel wall.10
The inflammatory response of SMCs involves a number of proteins of the signal cascade, including the inducible transcription factors c-Jun and c-Fos.11 These are expressed at very low levels in quiescent SMCs but can be induced by stimulating SMCs with different agents, such as angiotensin II12 or platelet-derived growth factor.13 When activated, c-Jun and c-Fos can dimerize to form activator protein-1 (AP-1), a transcription factor complex.14
Expression and activation of AP-1 proteins is tightly controlled by mitogen-activated protein (MAP) kinases, such as the c-Jun amino-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK), which play a pivotal role in signal transduction.15 16 JNK and ERK are rapidly activated by dual phosphorylation at conserved tyrosine residues by a number of environmental and cellular stresses.17 18 19 Also, reactive oxygen species (ROS) have been reported to induce MAP kinase activity.20 The present study investigated whether ET-1–mediated MAP kinase and AP-1 activation in SMCs were dependent on the generation of ROS.
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Methods |
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Materials
ET-1 was purchased from Boehringer-Mannheim, BQ 123 was from Alexis, and N-acetyl-L-cysteine (NAC) was from Boehringer-Ingelheim. Diphenylene iodonium (DPI), pertussis toxin, cholera toxin, phenylmethylsulfonyl fluoride, Nonidet P-40, and albumin bovine fraction V were from Sigma. Collagenase, elastase, and trypsin soybean inhibitor were obtained from Worthington. The JNK kinase assay and the phosphorylated ERK polyclonal antibody were from New England Biolabs. The ERK antibody was from Upstate Biotechnology; horseradish peroxidase–conjugated goat anti-rabbit immunoglobulin, from Dianova; and smooth muscle
-actin
antibody, diamidinophenylindole (DAPI), Pefabloc, and E-64, from
Boehringer-Mannheim. c-Jun and c-Fos antibodies for
immunofluorescence were gifts from Dr R. Bravo,
Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, NJ. c-Jun and c-Fos antibodies for supershift assays
were from Santa Cruz; enhanced chemiluminescence detection reagents and
Hyperfilm, from Amersham International; and
2',7'-dichlorofluorescein (DCF) diacetate
(H2DCF-DA), from Molecular Probes Europe. Protein
G-Sepharose 4 Fast Flow was purchased from Pharmacia Biotechnology. All
tissue culture material was from Eurobio.
Cell Preparation and Culture
Rat SMCs were isolated from aortas of male Sprague-Dawley rats
(aged 6 weeks, 200 g) by modification of a previously described
technique.21 Briefly, the intima and adventitia were
dissected, and the media was digested with 0.1%
collagenase, 0.05% elastase, 0.375 mg/mL trypsin
inhibitor from soybean, and 2 mg/mL albumin
fraction V. The cells were cultured in DMEM with FCS (10%
[vol/vol]), penicillin (100 U/mL)/streptomycin (100 µg/mL), and
2 mmol/L L-glutamine. The cells reacted with a smooth
muscle -actin antibody that selectively recognizes SMCs but does not
react with endothelial cells or fibroblasts. The
cultures were maintained at 37°C in a humidified atmosphere of 5%
CO2. Cells were grown as subconfluent monolayers
and used in passages 3 to 6. Before the experiments, the cells were
washed with PBS and grown in serum-free medium (0.1% BSA in DMEM) for
48 hours to render quiescent SMCs. Cells were then stimulated for
different periods of time with ET-1 alone or together with different
agonists. For immunofluorescence, the cells were
grown on coverslips.
Analysis of MAP Kinases
Western Blot
After stimulation, SMCs were washed twice with ice-cold PBS,
lysed with 500 µL ice-cold cell buffer (l20 mmol/L Tris-HCl [pH
7.4], 150 mmol/L NaCl, 1 mmol/L EDTA, 1 mmol/L EGTA,
1% [wt/vol] Triton X-100, 1 mmol/L glycerol phosphate, 1
mmol/L Na3VO4, 2.5
mmol/L sodium pyrophosphate, 1 µg/mL leupeptin, and l mmol/L
phenylmethylsulfonyl fluoride). Lysates were kept on ice for 30
minutes, sonicated 3 times for 10 seconds, and centrifuged
(4°C for 10 minutes at 13 000g). Protein concentrations
were determined by using a bicinchoninic acid protein assay kit from
Pierce according to the manufacturer’s protocol.
The soluble SMC lysates (10 µg per lane) were subjected to 10% SDS-PAGE as described.22 After electrophoretic transfer to nitrocellulose (Schleicher & Schuell), nonspecific binding sites were blocked with 5% nonfat milk powder in TBST buffer (150 mmol/L NaCl, 10 mmol/L Tris-HCl, and 0.1% Tween 20 [pH 8.0]). The primary antibody was diluted in blocking solution (1:1000 for anti–phospho-ERK) and incubated with the membrane overnight at 4°C. After a wash in TBST, the nitrocellulose was incubated with horseradish peroxidase–conjugated secondary antibody (1:10 000 in TBST) at room temperature for 60 minutes. Antibody binding was determined by using the enhanced chemiluminescence detection system according to the manufacturer’s instructions. Exposures were recorded on Hyperfilm for 10 seconds to 3 minutes and quantified by use of a densitometer (Bio-Rad). Multiple comparisons were evaluated with ANOVA, followed by the Fisher protected least significant difference method. A value of P<0.05 was considered statistically significant.
Kinase Assays
The JNK kinase assay was performed according to the
manufacturer’s protocol. For the assay, 200 µg of protein from SMC
lysates was incubated with 2 µg glutathione-S-transferase
(GST)–c-Jun protein beads overnight at 4°C. Complexes were
collected, washed, and resuspended in 50 µL kinase lysis buffer with
100 µmol/L ATP and incubated at 30°C for 30 minutes. Reactions
were terminated with sample buffer, and 25 µL of the supernatants was
subjected to 10% SDS-PAGE and Western blot as described above, with
phospho-c-Jun antibody used for the detection of JNK substrate.
Immunofluorescence
After stimulation, SMCs grown on coverslips were fixed with
methanol (5 minutes at -20°C) and acetone (1 minute at -20°C).
Coverslips were washed with PBS and incubated with primary antibodies
against c-Jun (1:10 000) and c-Fos (1:20 000) at room temperature for
60 minutes. After several washes, cells were incubated with secondary
antibody (Texas red–conjugated goat anti-rabbit IgG, 1:300) and DAPI
(1:1000 in PBS) at room temperature for 60 minutes. Coverslips were
then mounted with glycerogelatin. Fluorescence microscopy was
carried out on a Zeiss Axioplan microscope with a rhodamine filter set.
DAPI staining was visualized with use of a DAPI filter. Photographs
were obtained with Kodak black and white 400 ASA film.
Intracellular Redox State
Intracellular ROS production was measured by the method
of Bass et al.23
2',7'-Dichlorodihydrofluorescein
diacetate (H2DCFH-DA) is a nonpolar compound that
is converted into a nonfluorescent polar derivative
(H2DCFH) by cellular esterases after
incorporation into cells. H2DCFH is rapidly
oxidized to the highly fluorescent DCF in the presence of
intracellular hydrogen peroxide and peroxidases.23
Briefly, cells were incubated 30 minutes at 37°C with 5 µmol/L
H2DCF-DA in HBSS-HEPES. Cells were stimulated,
and the fluorescence intensity of 5 groups of 15 to 20 cells
for several time points was measured by confocal scanning microscopy
(Zeiss; excitation 488 nm, emission 513 nm). Intensity was measured for
each group from the fluorescence image, and the relative
fluorescence intensity was taken as the average of 5
values.
Preparation of Nuclear Extracts
For the electrophoretic mobility shift assay, nuclear protein
extracts were prepared according to the method of Schreiber et
al,24 with minor modifications. After ET-1 stimulation,
2x10-6 cells were washed twice with ice-cold
PBS and scraped into 400 µL of hypotonic buffer (10 mmol/L HEPES
[pH 7.9], 10 mmol/L KCl, 0.1 mmol/L EDTA, 0.1 mmol/L
EGTA, and 2 mmol/L dithiothreitol) supplemented with protease and
phosphatase inhibitors (5 µg/mL E-64, 1 mmol/L NaF,
0.2 mmol/L Na3VO3, and
0.5 mg/mL Pefabloc) and incubated 15 minutes on ice. Then 25 µL of
10% Nonidet P-40 was added, and the tubes were vigorously vortexed for
10 seconds. The nuclei were pelleted by centrifugation
at 14 000 rpm for 1 minute at 4°C. The nuclear pellets were
resuspended in 50 µL cold buffer (20 mmol/L HEPES [pH 7.9],
0.4 mol/L NaCl, 1 mmol/L EDTA, 1 mmol/L EGTA, 2 mmol/L
dithiothreitol supplemented with 5 µg/mL E-64, and 0.5 mg/mL
Pefabloc), and the tubes were rocked for 15 minutes at 4°C. After
centrifugation at 14 000 rpm for 5 minutes at 4°C,
the supernatants containing nuclear protein were collected and stored
at -80°C until use.
Gel Mobility Shift Assay
Nuclear extracts (2 µg each) were incubated with a labeled
oligonucleotide probe and 2 µg of
poly(dI-dC)–poly(dI-dC) in 20 µL of binding buffer (60 mmol/L
HEPES [pH 7.9], 50% glycerol, 20 mmol/L Tris-HCl [pH 8.0],
300 mmol/L KCl, 5 mmol/L EDTA, 100 µg/mL BSA, 2.5 mg/mL
Pefabloc, 25 µg/mL E-64, 5 mmol/L NaF, 1 mmol/L
Na3VO3, and 5 mmol/L
dithiothreitol) for 5 minutes at room temperature. The sequence of the
double-stranded oligonucleotide used in the present
study was as follows: consensus AP-1, 5'-CGCTTGAT GACTCAGCCGGAA-3'. The
probe was labeled with [
-32P]ATP by use of
T4 polynucleotide kinase. Binding reactions were resolved
on a 4% native polyacrylamide gel containing 1x TAE buffer
(25 mmol/L Tris, 25 mmol/L boric acid, and 0.5 mmol/L
EDTA). Gels were run at 150 V at 4°C for 2 to 3 hours, dried, and
exposed to x-ray film for 12 to 24 hours. In addition, a supershift
assay for AP-1 was carried out with the use of rabbit polyclonal
antibodies against c-Jun, c-Fos, and Fra-1. The specific antibody was
added to samples after the initial binding reaction between nuclear
protein extracts and 32P-labeled consensus
oligonucleotide, and the reaction was incubated at room
temperature for 1 hour.
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Results |
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ET-1 Induces Activation of JNK and ERK in Vascular SMCs
We used measurements of JNK and ERK activity to gauge the ability of ET-1 to activate vascular SMCs. In the kinase assays, ET-1 caused time- and concentration-dependent transient activation of JNK and ERK. JNK activity peaked 30 minutes after stimulation, achieving a maximum 2.5 times that of baseline (Figure 1
). ERK reached peak activation far more
rapidly (at 5 minutes after stimulation), with a 3-fold increase over
baseline (Figure 1). Resting activation levels of both kinases
were resumed within 60 minutes (Figure 1). Maximum activation of
both kinases was obtained by stimulation with ET-1 at
10-6 up to 10-10 mol/L,
with a maximum activation reached at 10-7 mol/L
(Figure 2).
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ET-1–Induced Activation of JNK and ERK Is Mediated by the
ET-A Receptor
Most effects of ET-1 on vascular SMCs are mediated by the
ET-1–type endothelin-A (ET-A) receptor. Preincubation of SMCs for 10
minutes with BQ 123 (10 µmol/L), a selective ET-1–type ET-A
receptor antagonist, inhibited ET-1–stimulated MAP kinase
activation (Figure 3). These findings are
consistent with previous observations in Rat-1 cells and
demonstrate the specificity of the ET-1 effect and the involvement of
the ET-A receptor.25
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Mechanism of ET-1–Induced Activation of MAP Kinases in
SMCs
To study whether ET-1 was able to induce the generation of ROS in
SMCs, we monitored the intracellular generation of ROS with DCFH-DA and
fluorescence microscopy. Exposure of SMCs to ET-1
(10-7 mol/L) resulted in an increase in DCF
fluorescence, beginning 10 minutes after stimulation (Figure 4). To test whether ROS played a role in
the regulation of JNK and ERK activity, cells were preincubated with
either DPI, an inhibitor of NADPH oxidase, or the radical
scavenger NAC. DPI (5 µmol/L, 60 minutes) suppressed activation
of JNK, whereas ERK activation by ET-1 was not significantly affected
(Figure 5). Similarly, NAC (5
mmol/L, 30 minutes) suppressed JNK activation but had no significant
impact on ERK activity (Figure 5). DPI or NAC alone did not
affect JNK or ERK expression (data not shown).
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To assess the role of G proteins in the induction of JNK and ERK, cells
were incubated with either pertussis toxin, an inhibitor of
Gi, or cholera toxin, an activator of
Gs. Treatment of the rat SMCs with pertussis
toxin (100 nmol/L, 16 hours) inhibited the activation of JNK but had no
significant effect on ET-1–mediated ERK activation (Figure 6). In contrast, cholera toxin (100
nmol/L, 16 hours) enhanced the ET-1–mediated activation of JNK but
showed only weak effects on ERK (Figure 6).
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ET-1 Induces c-Jun and c-Fos Protein
Induction of c-Jun and c-Fos protein was investigated by
immunofluorescence. The transcription factors
differed in response to ET-1 stimulation. c-Fos induction was maximal
at 30 minutes and began to decrease at 2 hours, whereas c-Jun protein
expression was slower and reached a maximum at 2 and 4 hours.
Expression of both transcription factors decreased to background levels
24 hours after stimulation (Figure 7).
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ET-1–Induced Activation of AP-1 DNA Binding
We examined whether ET-1 could activate AP-1 DNA binding
in SMCs. Nuclear extracts from ET-1–stimulated SMCs were incubated
with a 32P-labeled AP-1 consensus sequence. As
shown in Figure 8, ET-1 was able to
increase the DNA-binding activity of AP-1 after stimulation for 30
minutes, with a peak activation at 2 hours (
4-fold). An excess of
unlabeled AP-1 consensus oligonucleotide reduced the
signal intensity of the band associated with active AP-1, indicating
specific binding (data not shown). To determine whether ET-1–dependent
AP-1 activity was due to NAD(P)H oxidase, cells were pretreated with
the NAD(P)H oxidase inhibitor DPI (5 µmol/L, 60
minutes), resulting in a substantial reduction of ET-1–induced
DNA-binding activity of AP-1 (Figure 8). Furthermore, the extent
of involvement of c-Jun and c-Fos in AP-1 formation was also
investigated in ET-1–stimulated cells by the addition of antibodies
against either c-Jun, c-Fos, or Fra-1 to the binding reaction. With the
use of anti–c-Jun, this resulted in a shift of the binding complex to
a slower migrating species. The addition of antibodies against c-Fos or
Fra-1 did not lead to a significant shift in the AP-1 complex,
identifying c-Jun as the predominant protein in the AP-1 complex
(Figure 8).
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Discussion |
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For a number of years, a correlation between ET-1 plasma levels and atherogenesis has been recognized.1 Mechanisms usually ascribed to the atherogenic action of ET-1 include SMC mitogenic effects,26 27 the induction of tumor necrosis factor,28 stimulation of monocyte chemotaxis,29 increased secretion of interleukin-6 from endothelial cells,30 and induction of MAP kinases.8 9 So far, only limited data exist on the pathways leading to the activation of MAP kinases in SMCs by endothelin.8 9 31 32
It has been proposed that production of ROS by SMCs plays an important role in SMC activation and atherogenesis.33 34 35 ROS are very small, rapidly diffusible, and highly reactive. Therefore, superoxide and its metabolites can function as intracellular second messengers. Free radicals and redox stress are thought to participate in cellular signaling36 37 and regulate a number of important cellular events, including MAP kinase activation, gene expression, DNA synthesis, and cellular proliferation.37 38 39 As evidenced by a small number of studies, ET-1 can also induce ROS production in different cell types.40 41 42 Whether this mechanism is of importance for signal transduction in SMCs has not been reported to date. After establishing a time- and dose-dependent activation of MAP kinases by ET-1 that was consistent with previous findings,8 9 it was thus our aim to elucidate the role of ROS for ET-1–induced MAP kinase and transcription factor activation.
Experiments with the fluorescent marker DCFH-DA showed that stimulation with ET-1 induced a time-dependent generation of ROS in SMCs. The activation kinetics of the 2 MAP kinases, however, were quite different. In the present study, only JNK activation paralleled the time course of ROS formation; the activation of ERK was much more rapid. A similar slower response of JNK after ET-1 stimulation has also been observed in kidney mesangial cells31 and after angiotensin II stimulation of GN4 rat liver cells.43
Recent data by Ushio-Fukai et al35 indicate a ROS-dependent activation of JNK after stimulation of SMCs with angiotensin II, which, like ET-1, operates through G-protein receptors. In the present study, we report that as with angiotensin II, ET-1 stimulation of SMCs results in the activation of JNK via a mechanism sensitive to inhibitors of ROS formation, which leads to the speculation that JNK activation through G-protein agonists might be generally ROS dependent. Furthermore, Griendling et al33 have shown that angiotensin II can stimulate O2- levels in SMCs via NAD(P)H oxidase. Therefore, we examined the effect of DPI, a potent inhibitor of flavonoid-containing enzymes, such as NAD(P)H oxidase. DPI also inhibited ET-1 stimulation of JNK, which suggests the involvement of NAD(P)H oxidase for ROS formation.
The inhibition of JNK activation by pertussis toxin and the potentiation by cholera toxin in the present experiments corroborate a role for a classical G-protein–coupled pathway for ET-1–mediated JNK activity. Taken together, our data suggest that ET-1 initially engages with its ET-1A receptor; this occurrence is followed by the activation of Gi, which in turn causes activation of NADPH oxidase to generate ROS, which, downstream, results in the activation of JNK. This scheme is consistent with findings by Krieger-Brauer and Kather,44 who demonstrated that NADPH oxidase can be activated through Gi.
Common to the promoter regions of a number of proinflammatory genes is the presence of binding sequences for the inducible transcription factor AP-1.11 14 JNK phosphorylates 2 serine residues in the presumptive activation domain of c-Jun, increasing the transcriptional activity of the AP-1 complex.45 The JNK substrate c-Jun forms homodimers or heterodimers with c-Fos to form the AP-1 transcription factor. Vascular SMCs express inducible AP-1 activity.46 In the present study, we now provide evidence for a radical-dependent induction of AP-1 activity by ET-1. Consistent with the finding that the activated AP-1 complex contained mostly c-Jun, we could demonstrate an accompanying strong induction of c-Jun protein expression by ET-1, which at 2 and 4 hours was more marked than the induction of c-Fos. Furthermore, AP-1 activation was sensitive to ROS inhibition, illustrating the radical-dependent induction of AP-1–regulated gene transcription. In summary, the present data demonstrate that the generation of ROS, via flavonoid oxidases, by ET-1 may be a link between hormone-receptor interaction, stimulation of JNK activity, and downstream events. ROS may serve as important signaling molecules, exerting a concentration-dependent effect on gene expression through MAP kinase activation during atherogenesis. Taken together, these data can also serve to explain, in part, the beneficial antiatherogenic actions of endothelin antagonists and antioxidants because they may suppress inflammatory responses in the vessel wall.
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Acknowledgments |
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This study was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 320).
Received June 8, 1999; accepted November 10, 1999.
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