© 2000 American Heart Association, Inc.
Vascular Biology |
Role of p38 Mitogen-Activated Protein Kinase in Neointimal Hyperplasia After Vascular Injury
From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Correspondence to Akira Matsumori, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8397, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp
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Abstract |
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Abstract—p38 mitogen-activated protein kinase (MAPK) is involved in intracellular signals that regulate a variety of cellular responses during inflammation. However, the role of p38 MAPK in atherosclerosis, a chronic inflammatory disorder, remains uncertain. The aim of the present study was to examine the role of p38 MAPK in the development of neointimal hyperplasia in balloon-injured rat carotid arteries. Immunohistochemical studies indicated that p38 MAPK was rapidly activated in the majority of medial cells in injured arterial walls. Rats treated with FR167653, a selective inhibitor of p38 MAPK, at a dosage of 10 mg · kg–1 · d–1, had a 29.4% lower intima-to-media ratio than the untreated controls at 14 days after balloon injury (P<0.05). The percentage of proliferating nuclear antigen–positive cells in the media at 48 hours was significantly lower in the FR167653-treated group than in the control group. Quantitative competitive reverse transcription–polymerase chain reaction analysis revealed that interleukin-1ß mRNA expression in arteries was significantly inhibited by FR167653 (to 18.1% of control, P<0.05) at 8 hours after balloon injury. Moreover, p38 MAPK activation and interleukin-1ß production by lipopolysaccharide-stimulated vascular smooth muscle cells were inhibited by FR167653 in a concentration-dependent manner in vitro. These results indicate that p38 MAPK is activated in vascular walls after injury and promotes neointimal formation and suggest that selective inhibition of p38 MAPK may be effective in the prevention of restenosis after percutaneous transluminal coronary angioplasty.
Key Words: p38 mitogen-activated protein kinase • vascular smooth muscle cells • interleukin-1ß • angioplasty • coronary restenosis
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Introduction |
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Balloon angioplasty is widely used to treat atherosclerotic coronary artery disease. However, restenosis after angioplasty continues to limit the long-term success of the procedure.1 This accelerated form of atherosclerosis results from inflammatory and proliferative responses of the vascular wall to mechanical injury2 and is in part attributable to neointimal hyperplasia. Vascular cells, such as vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), and infiltrating inflammatory cells, including monocytes/macrophages and T-lymphocytes, play important roles in neointimal hyperplasia.
p38 mitogen-activated protein kinase (MAPK) is a new
member of the MAPK superfamily that is involved in intracellular
signaling pathways in various cell types. p38 MAPK regulates cellular
responses to a variety of cellular stresses, such as heat shock,
hyperosmolarity, ultraviolet radiation, the endotoxin
lipopolysaccharide (LPS), and the proinflammatory
cytokines, including interleukin (IL)-1ß and tumor necrosis
factor
(TNF)-
.3 4 5
The activation of p38 MAPK leads to the activation of
monocytes/macrophages,3
T-lymphocytes,6 and
VSMCs7 and the
production of proinflammatory cytokines, such as
IL-1ß and TNF-, by these
cells.8 These in
vitro observations suggest an important role of p38 MAPK in the
pathogenesis of atherosclerosis, although its role in
vivo remains uncertain.
We hypothesized that mechanical vascular injury induces the direct activation of p38 MAPK within the vascular wall and eventually leads to the development of neointimal hyperplasia. The results of the present study show that p38 MAPK is rapidly activated in the injured walls of rat carotid arteries and that its inhibition reduces IL-1ß gene expression, proliferative response of medial VSMCs, and neointimal hyperplasia.
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Methods |
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Biochemicals
FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate) was synthesized at Fujisawa Pharmaceutical Co, Ltd.9 LPS from Escherichia coli 055:B5 was purchased from Difco Laboratories. Phospho-p38 MAPK antibody (Ab), immobilized phospho-p38 MAPK monoclonal Ab (MAb), ATF-2 fusion proteins, and phospho-ATF-2 Ab were obtained from New England BioLabs. Enhanced chemiluminescence (ECL) Western blotting detection system were obtained from Amersham Pharmacia Biotech. Goat anti-p38 MAPK Ab and donkey anti-goat IgG horseradish peroxidase (HRP) were purchased from Santa Cruz Biotechnology.
Balloon Injury of Rat Carotid Arteries
Eleven- to 12-week-old male Sprague-Dawley rats were
anesthetized, and the endothelium of the left
common carotid artery was denuded with a 2F Fogarty embolectomy
catheter (Baxter Healthcare), as previously
described.10
In the in vivo experiments with FR167653, actively treated rats received the drug orally, dissolved in drinking water, and control rats received drinking water only. Both regimens were administered every 12 hours, starting 3 days before carotid arterial injury and continuing until death. No apparent toxic effects were observed in rats treated with FR167653 at doses of 3 or 10 mg · kg–1 · d–1. All FR167653-treated animals remained healthy and had an appropriate increase in body weight throughout the period of the in vivo experiments.
Immunohistochemical Staining
Immunohistochemical staining for
phosphorylated p38 MAPK was performed to examine the
activation of p38 MAPK in injured arterial walls. Ten
minutes after balloon injury, the nontreated rats were
anesthetized, perfused with saline that had been precooled at
4°C, and perfusion-fixed with 10% neutral buffered formalin at
90 mm Hg. The carotid arteries were gently removed, fixed
further, and embedded in paraffin. The tissue was sliced into
4-µm-thick slices and processed for immunohistochemical
analysis with the use of the avidin biotin–alkaline
phosphatase complex (Vector Laboratories) system with biotinylated goat
anti-rabbit IgG (DAKO) as secondary Ab at a dilution of 1:300. Alkaline
phosphatase was developed with the use of Vector Red (Vector
Laboratories). Rabbit anti-phospho-p38 MAPK polyclonal Ab diluted 1:50
was used as the primary Ab. The sections were counterstained with
methyl green. For negative controls, normal rabbit IgG (DAKO) was used
instead of primary Ab to stain the injured arteries.
To assess the effects of FR167653 (10 mg · kg–1 · d–1) on the initial medial proliferation of VSMCs, immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) was performed as previously described.10 The carotid arteries were removed 48 hours after injury, fixed with 10% neutral buffered formalin, and embedded in paraffin. The embedded arteries were cut into six 4-µm-thick sections from proximal, middle, and distal segments perpendicular to the short axis and deparaffinated. Immunohistochemistry was performed according to an avidin biotin-horseradish peroxidase complex method (Vector Laboratories) with biotinylated rabbit anti-mouse IgG diluted 1:500 (DAKO). Peroxidase was visualized with 3',3'-diaminobenzidine. Mouse MAb against PCNA (PC10, YLEM Srl) was used as the primary Ab at 1:50 dilution. The sections were counterstained with hematoxylin. In control animals, the primary Ab was omitted. Cell number was counted at a x400.
Light Microscopic Examination and Morphometry
of Neointima
In these experiments, FR167653 was administered at
dosages of 3 or 10
mg · kg–1 · d–1.
On day 14 after arterial denudation, the rats were
anesthetized before the injection of 200 µL of 2% Evans’
blue dye in PBS and heparin (100 U/rat) into the tail vein. The animals
were perfusion-fixed with 10% neutral buffered formalin as previously
described.10 The
carotid arteries were removed and fixed further. The central portions
of the blue-stained areas were divided into five 1-mm-thick specimens
embedded in paraffin. The sections were stained with elastic-van
Gieson’s stain. The intimal and medial areas were measured with an
image analyzer (LUZEX3U; Nikon). In each animal, the mean
intimal and medial areas of each artery were calculated from these 5
sections.
RNA Preparation and cDNA Synthesis
Rats assigned to the treatment group received 10
mg · kg–1 · d–1
FR167653. The carotid arteries were harvested at 1, 2, 4, 8, 24, 72, or
120 hours after balloon injury (n=5 at 8 hours and n=3 at all other
time points). Intact left common carotid arteries of Sprague-Dawley
rats (n=3 at 0 hour) were used as controls. Total RNA was prepared from
the arteries according acid to the guanidinium
thiocyanate-phenol-chloroform-isoamylalcohol isolation method, and 0.3
µg of total RNA template was subjected to first-strand cDNA synthesis
with dNTP (Takara) and Moloney murine leukemia virus reverse
transcriptase (GIBCO BRL), under the conditions recommended by the
manufacturer. The synthesized cDNA was stored at
-20°C.
Quantitative Competitive PCR
To quantitatively estimate IL-1ß mRNA expression,
competitive PCR was performed as previously
described.10 A
constant amount of cDNA was amplified by PCR with serially diluted
nonhomologous DNA fragments that contained primer template sequences as
an internal control, according to the manufacturer’s instructions (PCR
MIMIC Construction Kit; Clontech Laboratories Inc).
To determine the exact amount of the target mRNA species, the internal control was diluted 2-fold. A sense primer (A) and an antisense primer (B) were synthesized for each with use of the published cDNA sequences for rat IL-1ß11 and rat GAPDH12 as follows: IL-1ß (A), 5'-ATGGCAACTGTCCCTGAACTCAACT-3'; IL-1ß (B), 5'-CAGGACAGGTATAGATTCAACCCCTT-3'; GAPDH (A), 5'-TGAAGGTCGGTGTGAACGGATTTGGC-3'; and GAPDH (B), 5'-CATGTAGGCCATGAGGTCCACCAC-3'.
Each PCR contained 100 µmol/L dNTP, 0.5 µmol/L
concentration of each specific primer, 10 mmol/L Tris-HCl (pH
8.3), 50 mmol/L KCl, 1.5 mmol/L MgCl2,
0.001% gelatin, and 0.25 U Taq polymerase
(Perkin–Elmer Cetus) in a volume of 25 µL.
[-32P]dCTP was included in the reaction
to quantify the PCR products. Both IL-1ß and GAPDH cDNA were
analyzed with 40 and 32 cycles of amplification in a thermal
cycler (Perkin–Elmer Cetus). The cycle for IL-1ß cDNA consisted of
denaturation at 94°C for 60 seconds, annealing at 55°C for 60
seconds, and extension at 72°C for 90 seconds. The cycle for GAPDH
cDNA consisted of denaturation at 94°C for 60 seconds, annealing at
50°C for 60 seconds, and extension at 72°C for 90 seconds. A
portion of each PCR product was electrophoresed on a 5%
polyacrylamide gel, and the densitometric values of
32P-labeled target and internal control were
analyzed with the FUJIX bioimaging analyzer (BAS 2000;
Fuji Photo Film Co, Ltd). The molar ratio of target to internal control
was calculated as target/internal control=(VT/VC)x(CC/CT), where VT
and VC represent the densitometric value of the PCR product
from target and internal control, respectively, and CC and CT
represent the dCTP content in the PCR product from internal
control and target. The amount of target gene was determined as that of
the internal control at the point of an equal molar ratio between
target and internal control. The amounts of IL-1ß were divided by the
amounts of GAPDH to correct for the efficiency of cDNA
synthesis.
Cell Culture
VSMCs were isolated according to a previously
described explant
method,13 from
thoracic aortas of 8- to 10-week-old male Sprague-Dawley rats. Cells
were grown in DMEM (Nissui) supplemented with 10% FCS, 100 µg/mL
streptomycin, and 100 U/mL penicillin (GIBCO BRL) in a humidified
atmosphere (5% CO2/95% air) at 37°C. Cells
were used between passages 4 and 10 for all
experiments.
Immunoprecipitation and p38 MAPK Activity
Assay
VSMCs cultured at 80% to 90% confluence in 100-mm
dishes were made quiescent through incubation with DMEM supplemented
with 0.1% FCS for 24 hours. Cells were treated in the absence or
presence of FR167653 for 2 hours and then stimulated with LPS (1
µg/mL) at 37°C. After stimulation, the cells were washed twice with
cold PBS on ice, scraped, and extracted in 500 µL of cold lysis
buffer that contained 20 mmol/L Tris, pH 7.5, 150 mmol/L
NaCl, 1 mmol/L EDTA, 1 mmol/L EGTA, 1% Triton X-100,
2.5 mmol/L sodium pyrophosphate, 1 mmol/L
ß-glycerophosphate, 1 mmol/L sodium orthovanadate, 1 µg/mL
leupeptin, and 1 mmol/L phenylmethylsulfonyl fluoride. The
extracts were sonicated and centrifuged at
15 000g for 10 minutes at 4°C, and the supernatants
were immediately used for immunoprecipitation or stored at -80°C.
p38 MAPK activity was measured with use of the p38 MAPK assay kit (New
England Biolabs). Two hundred micrograms of cell lysates (400 µg
protein) was incubated with 20 µL of immobilized
phospho-p38 MAPK MAb overnight at 4°C. The beads were washed twice
with 500 µL of lysis buffer and twice with 500 µL of kinase buffer
containing 25 mmol/L Tris, pH 7.5, 5 mmol/L
ß-glycerophosphate, 2 mmol/L dithiothreitol, 0.1 mmol/L
sodium orthovanadate, and 10 mmol/L MgCl2
and then resuspended to 50 µL with kinase buffer. ATP (200 µmol/L)
and ATF-2 (2 µg), as substrate, were added to the suspension. The
kinase activity was assayed for 30 minutes at 30°C, terminated by the
addition of 3x SDS sample buffer, and boiled for 5 minutes. The
samples were resolved on 12% SDS-PAGE, electroblotted onto PVDF
membranes, and probed with phospho-ATF-2 Ab (1:1000). The
immunoreactivity was detected with enhanced chemiluminescence and
determined with densitometry (NIH Image 1.61).
Immunoblotting
VSMCs lysates were prepared as described earlier. The
proteins (30 µg) were separated on 10% polyacrylamide gels
with SDS-PAGE followed by Western blotting with goat anti-p38 MAPK Ab
(1:1500). Immunocomplexes were visualized through ECL detection with
HRP-conjugated anti-goat Ab used as secondary Ab
(1:1000).
Cytokine Production by
VSMCs
Cultured VSMCs were trypsinized, suspended in DMEM
containing 10% FCS, and seeded onto 24-well plates. The VSMCs, grown
to confluence, were incubated in DMEM containing 0.1% FCS for 24
hours. After treatment with or without FR167653 for 2 hours, VSMCs were
stimulated with LPS (1 µg/mL). After 24 hours of incubation, the
supernatants were harvested. IL-1ß in the supernatants was determined
with specific ELISA kits (Biosource International). All measurements
were performed in duplicate.
Statistical Analysis
Values are expressed as mean±SEM. Multiple
comparisons were performed by ANOVA. Paired data were analyzed
by the 2-tailed unpaired Student’s t test. Values for
relative IL-1ß mRNA levels at 8 hours after injury were compared
using the Mann-Whitney U test, because they were
nonparametrically distributed. A P value
of <0.05 was considered statistically
significant.
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Results |
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Immunolocalization of Phosphorylated p38 MAPK in Injured Carotid Arteries
No positive immunostaining was detectable in intact carotid arteries (please see Figure I, published online at http://atvb. ahajournals.org). In contrast, the majority of medial cells were intensely stained for phosphorylated p38 MAPK in sections of the arteries obtained at 10 minutes after balloon injury (Figures 1A
and I). A representative stained
section from a control experiment is shown in
Figure 1B.
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Effects of Inhibition of p38 MAPK on
Neointimal Hyperplasia
Significant neointimal hyperplasia
was observed in all left common carotid arteries 14 days after injury
(Figures 2A and 2B). The oral administration of FR167653
inhibited intimal thickening
(Figures 2C and 2D). In the group treated with 10
mg · kg–1 · d–1,
neointimal hyperplasia was significantly inhibited compared
with the untreated group. The mean intima-to-media ratio was reduced to
0.697±0.057 versus 0.988±0.066 in the untreated group,
representing a 29.4% inhibition (P<0.05,
Figure 3).
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Effect of Inhibition of p38 MAPK on Initial
Medial Proliferation After Mechanical Injury
At 48 hours after injury, immunohistochemical staining
with anti-PCNA Ab showed a significant decrease in the population of
medial proliferating cells in the FR167653-treated group compared with
the untreated group
(Table).
The percentage of PCNA-positive cells was 19.0±0.9 in the
FR167653-treated group versus 25.4±1.2 in the untreated group
(P<0.05).
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IL-1ß Gene Expression in Injured
Arteries
IL-1ß mRNA in the balloon-injured arteries was
measured with quantitative competitive RT-PCR. Coamplification of
sample cDNA with serially diluted mimic cDNA showed a close correlation
between the amount of mimic cDNA and the target cDNA–to–mimic cDNA
ratio for each reaction (please see Figure II, published online at
http://atvb.ahajournals.org). The induction of IL-1ß gene expression
was demonstrable as early as 1 hour and peaked at 8 hours after injury
in the injured arterial wall of the untreated rats. IL-1ß
gene expression level decreased at 24 hours, and although it was
relatively low but upregulated, IL-1ß gene expression was still
present at 120 hours after injury
(Figure 4).
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Effect of Inhibition of p38 MAPK on IL-1ß
Gene Expression in Injured Carotid Arteries
IL-1ß gene expression in injured carotid arteries
peaked at 8 hours after injury
(Figure 4
). At 8 hours after injury, the relative gene
expression of IL-1ß in the FR167653 (10
mg · kg–1 · d–1)
treatment group was reduced to 18.1% of that measured in the
vehicle-treated, control group (P<0.05, Figure
II).
p38 MAPK Activity by LPS-Stimulated
VSMCs
LPS-stimulated VSMCs were used in vitro to evaluate the
inhibitory effect of p38 MAPK activity by FR167653. First,
the time course of p38 MAPK activity after LPS stimulation at a
concentration of 1 µg/mL was determined. LPS induced a rapid
activation of p38 MAPK in VSMCs, reaching its peak at 15 minutes and
returning to baseline at 120 minutes (please see Figure III, published
online at http://atvb.ahajournals.org). At 15 minutes, the amount of
p38 MAPK activation by LPS in VSMCs was 3.1±0.3-fold that measured in
unstimulated controls. In addition, LPS-induced p38 MAPK activity was
inhibited by FR167653 in a concentration-dependent manner, reaching a
63.3% reduction at 0.1 µmol/L (P<0.01 versus
stimulated control; Figures III and
5).
The total protein level of p38 MAPK in these p38 MAPK activity
experiments was not significantly modified. Comparable results were
reproduced in 3 separate experiments.
IL-1ß Production by LPS-Stimulated
VSMCs
LPS caused an increase in IL-1ß
production by VSMCs at a concentration of 1 µg/mL
(103.4±0.45 versus 18.1±0.1 pg/mL at baseline,
P<0.01). IL-1ß production was inhibited by
FR167653 in a concentration-dependent manner, reaching 75.9% reduction
at 1 µmol/L (P<0.01 versus stimulated control;
Figure 6). Three separate experiments were
performed.
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Discussion |
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The activation of p38 MAPK is involved in intracellular signaling pathways that lead to a variety of cellular responses, including inflammatory cytokine production, cell growth, cell differentiation, and cell death. Previous in vitro studies have shown that the activation of p38 MAPK is induced in VSMCs and ECs by proatherogenic stimuli such as mechanical stress, TNF-
or
IL-1ß, or oxidative
stress.7 14 15
In the present study, FR167653, a selective
inhibitor of p38 MAPK, was used to examine the effects of
p38 MAPK inhibition in vivo on the acute (ie, cytokine gene
expression) and chronic (ie, neointimal hyperplasia)
responses to mechanical injury in the arterial wall.
FR167653 possesses the pyridine and fluorophenyl rings that are
essential for binding to p38 MAPK. Recent crystallographic studies have
revealed that inhibitors of p38 MAPK compete with ATP for
binding to p38 MAPK via these structures and produces a selective,
potent inhibition of p38 MAPK
activity.16 p38 MAPK
has been prominently implicated in the development of
atherosclerosis.17
It regulates the production of several cytokines or
chemokines, such as IL-1ß, IL-6, TNF-, and MCP-1, that play
important roles in
atherogenesis.8 18 19
Among them, we focused on IL-1ß to examine the role of p38 MAPK in
acute inflammatory responses.
The results of the in vivo experiments revealed that p38 MAPK inhibition significantly reduces neointimal hyperplasia in injured rat carotid arteries. This may be in part due to an inhibition of the initial medial VSMC proliferation, although inhibition of initial medial cell proliferation through another method was unsuccessful in limiting neointimal hyperplasia.20 Injured arterial walls contain a variety of mitogens for VSMCs,20 21 with the main one being PDGF-BB.21 In vitro, however, FR167653 did not inhibit the mitogenic response of VSMCs to PDGF-BB (unpublished observation). Therefore, the attenuation of medial VSMC proliferation by FR167653 in vivo may not be a result of the blockade of p38 MAPK activation by PDGF-BB. Besides the inhibitory effect of p38 MAPK on the mitogenic response of VSMCs, a decrease in IL-1ß gene expression may also be associated with reduced neointimal hyperplasia. In pigs, mechanical injury induces an abundant expression of IL-1ß mRNA throughout the coronary arterial walls.22 A particularly prominent expression of IL-1ß gene was found in inflammatory cells accumulated in the adventitia.22 Thus, in injured arterial walls exposed to endothelial denudation, both adventitial inflammatory cells and medial smooth muscle cells may be major sources of IL-1ß.
The precise role of IL-1ß in the development of
neointimal hyperplasia is uncertain; other investigators,
however, have reported that both IL-1 and IL-1ß genes are
expressed in human atherosclerotic
lesions23 and in
LPS-stimulated rabbit vascular
tissue.24
Furthermore, chronic treatment with exogenous IL-1ß induced
coronary intimal hyperplasia in a porcine
model.25 These
observations suggest that IL-1ß plays an important role in chronic
inflammation of the arterial wall and promotes
neointimal hyperplasia in rat balloon-injured carotid
arteries.
In our model, the activation of p38 MAPK was required for the induction of IL-1ß mRNA in injured arteries, because pharmacological inhibition of p38 MAPK markedly reduced IL-1ß gene expression at its peak. The inhibitory effect of p38 MAPK inhibition on IL-1ß production by VSMCs was also observed in the in vitro experiments, and the decrease of IL-1ß production correlated with a decrease in p38 MAPK activity. This also suggests an important role of the intracellular signaling pathway that involves p38 MAPK in IL-1ß gene expression in VSMCs. Other investigators recently reported that p38 MAPK regulates the production of IL-1ß at the transcriptional and translational levels in monocytes.8 26 In the transcriptional regulation, p38 MAPK phosphorylates and activates transcriptional factors, such as ATF-2, CHOP, and MEF2C, thereby inducing cytokine gene expression.17 p38 MAPK may play a similar regulatory role in IL-1ß gene expression in VSMCs.
Previous studies have suggested the existence of a positive feedback loop between p38 MAPK and IL-1ß.5 8 Accordingly, interruption of this positive feedback loop is one of the possible mechanisms responsible for the inhibitory effects of p38 MAPK inhibition on IL-1ß gene expression, as well as for neointimal hyperplasia.
Thus, in the present study, multiple effects were identified of p38 MAPK inhibition on the acute responses of arterial walls to mechanical injury. Redundant and complicated use of intracellular signaling pathways by numerous cytokines and growth factors may prevent treatments that target these growth factors from being successful in the prevention of restenosis. Instead, targeting downstream intracellular signaling molecules such as p38 MAPK may be a more appropriate strategy in the development of new treatments aimed at the prevention of restenosis after angioplasty, because several signals from different receptors share similar intracellular signaling pathways, whereas a single intracellular signaling molecule is implicated in multiple cellular responses.27 28
In conclusion, we found that the activation of p38 MAPK is induced by mechanical injury of arterial walls and promotes neointimal formation. Further studies are needed to clarify the precise mechanism by which p38 MAPK promotes neointimal hyperplasia and to test the effects of a selective inhibition of p38 MAPK in the prevention of restenosis after balloon angioplasty.
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Acknowledgments |
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This work was supported by a research grant from the Ministry of Health and Welfare of Japan and a grant-in-aid for general scientific research from the Ministry of Education, Science, and Culture of Japan. We thank Fujisawa Pharmaceutical Co, Ltd, for generously providing FR167653 needed to perform the experiments. We are grateful to Shoko Sakai for preparation of the manuscript.
Received February 15, 2000; accepted August 10, 2000.
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