|A Central Role of PTP1B in Hyperinsulinemia-Enhanced IL-6 Signaling in
Dedifferentiated Vascular Smooth Muscle Cells
|Department of Pharmacology, A.T, Still University, Kirksville, MO 63501, USA
||Dr. Yingzi Chang
Department of Pharmacology
A. T. Still
Kirksville, MO 63501, USA
|Received January 20, 2011; Accepted March 02, 2011; Published March 04, 2011
|Citation: Chang Y (2011) A Central Role of PTP1B in Hyperinsulinemia-Enhanced
IL-6 Signaling in Dedifferentiated Vascular Smooth Muscle Cells. J Diabetes Metab
|Copyright: © 2011 Yingzi Chang. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
|Hyperinsulinemia is associated with an increased risk of vascular restenosis after angioplasty. As a major proinflammatory
cytokine, interleukin-6 (IL-6) induces motogenic effects on vascular smooth muscle cells. Attenuation
of vascular injury-induced neointima thickening was observed by blocking STAT3 tyrosine phosphorylation, which is a
key component of IL-6 signaling. A non-receptor protein tyrosine phosphatase, PTP1B, plays a counter-regulatory role
in injury-induced neointima formation by inhibiting platelet-derived growth factor (PDGF)-induced smooth muscle cell
migration and proliferation. However, the role of IL-6, in association with hyperinsulinemia, with an increased risk of
vascular restenosis and the involvement of PTP1B in this process has never been studied. Using subcultured (passages
5-9) smooth muscle cells isolated from rat aortae, we found that: 1) chronic insulin treatment potentiated IL-6-induced
smooth muscle cell migration and STAT3 tyrosine phosphorylation; 2) chronic insulin dose-dependently suppressed
the baseline expression of endogenous PTP1B; 3) overexpressing wild-type PTP1B significantly attenuated whereas
C215S-PTP1B enhanced IL-6-induced STAT3 phosphorylation and smooth muscle cell migration. The aforementioned
results suggest that inhibition of baseline expression of PTP1B and subsequent potentiation of IL-6-stimulated vascular
smooth muscle migration may serve as a potential mechanism for increased risk of vascular restenosis after angioplasty
in patients with insulin resistance.
|Hyperinsulinemia; IL-6; PTP1B; Smooth muscle cells;
|Hyperinsulinemia, a major feature of type 2 diabetes and the metabolic
syndrome, is believed to be highly associated with the occurrence
of atherosclerosis and vascular restenosis [1-3]. In humans with insulin
resistance, the frequency of restenosis after coronary angioplasty is
significantly higher than those with normal insulinemia . Animals
with hyperinsulinemia show increased neointima formation caused by
vascular injury via potentiating smooth muscle cell migration and proliferation
[5-7]. The application of insulin sensitizers, such as synthetic
thiazolidinediones (STD), significantly reduces carotid artery intima/media thickness in patients with type 2 diabetes [8-10] and in animals
with induced carotid injury [11-14]. However, the underlying mechanisms
are not well understood. Recurrent stenosis after angioplasty is
the result of increased smooth muscle cell proliferation in the media
layer and migration to the intima in the wall of the vasculature. It is well
established that vascular inflammation in response to angioplasty-induced
injury is the initiator of increased neointima formation. Several
experimental and clinical observations indicate that up regulation of
pro-inflammatory cytokines in activated SMCs contributes to angioplasty-induced restenosis through promoting vascular smooth muscle
cell migration and proliferation, a manifestation of an inflammatory
wound healing process occurring in injured vessels [15-17]. Of the
many cytokines involved in injury-induced inflammation, IL-6 is the
major pro-inflammatory cytokine that contributes to vascular Injury-induced
neointima thickening . IL-6 is expressed and synthesized
by a variety of cell types implicated in intimal hyperplasia. These include
endothelial cells, macrophages, and smooth muscle cells. IL-6 induces a
motogenic effect on vascular smooth muscle cells [19,20]. A significant
correlation between the changes of IL-6 concentrations in the coronary
circulation after PTCA and the degree of restenosis has been observed
. Monitoring variations in IL-6 has been proposed as an inflammatory
marker to detect the early stage of cardiovascular diseases in order
to develop a beneficial strategy to prevent the progression of the diseases.
It was also reported that IL-6 induced the expression of acute phase
proteins and several other cytokines and growth factors, suggesting that IL-6 may serve as a major initiator to trigger inflammation cascade
responses that later lead to restenosis. One of the signal transduction
pathways that mediates IL-6-mediated cellular responses is gp130/JAK/
STAT cascade . The formation of IL-6 and the IL-6 receptor complex
promotes the recruitment of gp130, followed by activation of Janus
kinase (JAK). Activation of JAKs leads to tyrosine phosphorylation of
gp130 and recruitment of STAT3. STAT3 in turn becomes phosphorylated
and dimerized, and translocate into the nucleus, where it binds to
the target genes and regulates gene transcription and protein expression
, leading to cell migration and proliferation. Inhibition of excessive
IL-6 signaling by blocking the gp130/JAK/STAT pathway has become
a promising intervention to reduce inflammation. A recent study reported
that vascular injury increased STAT3 phosphorylation and that
blockade of gp130/STAT3 signaling decreased balloon injury-induced
STAT3 phosphorylation, reduced smooth muscle cell migration from
media to intima, and attenuated neointima formation , suggesting
that IL-6 plays a pivotal role in vascular injury-induced neointima formation
by activating gp130/STAT3 pathway. PTP1B is a non-receptor
protein tyrosine phosphatase that serves as a negative regulator in several
signal transduction pathways. PTP1B upregulation was observed
in a rat carotid artery injury model [24,25]. Transfection of PTP1B in
cultured vascular smooth muscle cells revealed inhibition of motogenic
effect in response to platelet-derived growth factor (PDGF) [26,27], by
abrogation of PDGF-induced receptor tyrosine phosphorylation. Over- expression of dominant negative PTP1B significantly potentiated vascular
injury-caused neointima formation . These findings indicate
that PTP1B plays a counter-regulatory role in injury-induced intimal
thickening by attenuating PDGF-induced smooth muscle cell migration
and proliferation. Although it is well established that an extensive
inflammatory reaction is associated with insulin resistance-related vascular
complication [28,29], that hyperinsulinemia increased the risk of
vascular restenosis after angioplasty, and that vessel wall inflammation
is the initial responder in vascular injury-induced restenosis, the role of
PTP1B in hyperinsulinemia-induced high frequency of vascular restenosis
and the involvement of PTP1B in regulation of pro-inflammatory
signaling have never been studied.
|Our current study was designed to test the hypothesis that chronic
hyperinsulinemia enhances vascular injury-induced restenosis by
suppressing the expression of endogenous PTP1B and subsequently
potentiating the motogenic effect of IL-6.
|Materials and Methods
|Smooth muscle cell cultures were prepared from adult male
Sprague-Dawley rats. Rats were sacrificed by inhalation of CO2. The
protocol for animal use was approved by the A.T. Still University Animal
Care and Use Committee by complying with the Guide for the Care
and Use of Laboratory Animals (Department of Health and Human
Services, NIH Publication No. 86-23, Revised 1996).
|Male Sprague-Dawley rats were purchased from Hilltop Lab
Animals Inc. (Scottdale, PA). DMEM and DMEM:Ham's F-12 (1:1)
medium and fetal bovine serum were obtained from Fisher Scientific
(Pittsburgh, PA); porcine pancreatic elastase and collagenase were
obtained from Worthington Biochemical (Lakewood, NJ); soybean
trypsin inhibitor, BSA (fraction V), bovine pancreatic insulin, protease
inhibitor cocktail, mouse IgG2a, human recombinant interleukin-6,
and all the chemicals were purchased from Sigma (St. Louis, MO);
antibodies directed against STAT3 and phospho-STAT3 (Tyr705 were
obtained from Cell Signaling (Boston, MA); PTP1B monoclonal
antibody was purchased from BD Biosciences (San Jose, CA); protein
G-Sepharose beads were from GE (Piscataway, NJ); and adenovirus
encoding EGFP(enhanced green fluorescent protein), human sequence
wild-type PTP1B, or dominant negative PTP1B (C215S-PTP1B) were
kindly donated by Dr. Aviv Hassid (University of Tennessee Health
Science Center, Memphis, TN).
|Vascular smooth muscle cells (VSMCs) were isolated from the
thoracic aortae of 100-125-g male Sprague-Dawley rats by enzymatic
dissociation following the published procedure  and grown in
DMEM/F12 supplemented with 10% (v/v) heat inactivated fetal
bovine serum, 100 units/ml penicillin, and 100 µg/ml streptomycin.
Cultures were maintained at 37°C in a humidified 95% air and 5% CO2
atmosphere. The experiments were performed by using subcultured
vascular smooth muscle cells between 5 and 9 passages by following
a previously published paper . The rationale for using subcultured
smooth muscle cells isolated from rat aorta is based on the evidence
that there are extensive phenotypic similarities among subcultured
aortic smooth muscle cells and the cells in neointima. Several studies
revealed that the smooth muscle cells isolated from neointima
showed morphologically and functionally similar characteristics to
the dedifferentiated smooth muscle cells [31,32]. Phenotypic changes
of smooth muscle cells from a differentiated to a more immature (or dedifferentiated) state after vascular injury allow the cells to replicate
and expand [33-35]. Furthermore, smooth muscle cells in intima
express the genes that represent the characteristics of developmental
stages of smooth muscle cells [36,37]. The changes of growth patterns
and gene expression, the major events that cause neointima formation
after vascular injury, are believed to be associated with the loss of
intracellular growth control . These data indicate that subcultured
cells are the appropriate model to mimic the cells in both media and
neointima in injured vessel wall.
|Measurement of cell motility
|VSMC motility was measured by cell wounding as described
previously . Briefly, confluent cells were subjected to a scratch of
about ~20 µm width made with a 10 µl sterile pipette tip. Pictures were
taken before and after 24 hour treatment by using a digital camera
from Scion Corporation (Frederick, MD). Images were analyzed by
using Image J software. Cell migration is expressed as distance covered
by cells during 24 hour incubation. 5 mM of hydroxyurea was used to
prevent cell proliferation .
|STAT3 phosphorylation measurement
|At the end of each treatment, cells were lysed on ice in a cold RIPA
buffer ( PBS, 1% Igepal CA630, 0.5% sodium deoxycholate, 0.1% SDS,
pH 7.2) containing a protease inhibitor cocktail (1 mM AEBSF, 0.8 µM
aprotinin, 20 µM leupeptin, 40 µM bestatin, 15 µM pepstatin A, 14 µM
E64) and 1 mM of sodium vanadate. STAT3 phosphorylation was
checked by either immunoprecipitation with anti-STAT3, followed by
probing with anti-phospho-STAT3 at Tyr 705, or direct western blot
probed with phospho-STAT3 antibody (as indicated in the legend).
Samples used to check tyrosine phosphorylation of STAT3 were
resolved by electrophoresis on 0.1% SDS and 10% polyacrylamide gels.
Total STAT3 was checked by stripping and reprobing the membranes
with anti-STAT3 to serve as loading controls. The antigen-antibody
complexes were detected using a Chemiluminescence reagent kit
(Perkin Elmer Life Science, Boston, MA).
|Adenoviruses expressing EGFP, wild-type PTP1B, or C215S-PTP1B
were generously donated by Dr. Aviv Hassid (University of Tennessee
Health Science Center). Adenoviral vectors were constructed by using
the technology developed by the University of Iowa. This technique
allows the generation of totally homogeneous adenoviral vectors that do
not require plaque purification. Briefly, relevant cDNAs were subcloned
into pShuttle, which serves as a transfer vector that allows homologous
recombination with viral backbone DNA. The Vector pShuttle contains
an extensive multiple cloning site, making it possible to subclone
most cDNAs into a site 3' from the CMV immediate/early promoter/enhancer with ease. Following preparation of recombinant pShuttle, the
vectors were linearized and co-transferred with viral backbone DNA
into HEK293 cells using the lipid transfer agent, Fugene-6. Following
several passages in 293 cells, sufficient adenovirus was obtained,
allowing purification to a high titer via an affinity purification step
using a kit from BD Inc. (Franklin Lakes, NJ)
|The differences between the treatments were analyzed by one way
analysis of variance (ANOVA) followed by post hoc test and student
t-test. A p value of less 0.5 was considered as a significant difference. All
the experiments were repeated at least three times.
|Chronic insulin treatment potentiates IL-6-induced vascular
smooth muscle cell migration
|To understand the role of IL-6 in insulin-enhanced vascular
injury-induced restenosis, we first tested the effect of chronic insulin
treatment on IL-6-induced vascular smooth muscle cell migration. It
should also be noted that insulin can, by itself, induce cell motility in
dedifferentiated cells if it is present at a sufficiently high level. Therefore,
for the present experiments, we titrated insulin concentration down
to the level (5 nM) at which it produced no significant increase in
motility in order to avoid a potential confounding effect of altered
baseline motility. As shown in (Figure 1) treatment of cells with IL-6
at the concentration of 20 ng/ml significantly stimulated vascular
smooth muscle cell migration. Pretreatment of the cells with the low
concentration of insulin significantly potentiated the motogenic effect
|Chronic insulin treatment potentiates IL-6-induced STAT3
phosphorylation in VSMCs
|Our next experiment was designed to study the signal transduction
pathway that is involved in the potentiation of the IL-6-stimulated
motogenic effect in cells treated with insulin. The experiment was carried
out by testing the effect of chronic insulin treatment on IL-6-induced
tyrosine phosphorylation of STAT3, a key event in IL-6 signaling. As
shown in (Figure 2A and 2B) and B, IL-6 stimulated STAT3 tyrosine
phosphorylation in a time- and dose-dependent manner. With the IL-6
concentration of 20 ng/ml, STAT3 tyrosine phosphorylation peaked at
the 30 min time point. Pretreatment with insulin (100 nM) for 24 hours
significantly potentiated IL-6-induced STAT3 tyrosine phosphorylation
(Figure 2C), suggesting that IL-6 may act as a mediator for insulinenhanced
vascular restenosis following angioplasty. We also tested the
effect of the low concentration of insulin (5 nM) on IL-6-induced STAT3
tyrosine phosphorylation and found that 5nM of insulin produced
similar effects on IL-6-stimulated STAT3 phosphorylation as those
produced by a higher concentration of insulin (Figure 2D). Therefore,
subsequent experiments were all carried out by using 100 nM of insulin.
|Chronic insulin treatment dose-dependently suppresses the
baseline expression of endogenous PTP1B in dedifferentiated
smooth muscle cells
|Our previous results showed that levels of PTP1B are significantly increased after vascular injury and over expression of dominant negative
PTP1B potentiates injury-induced neointima formation, indicating
that PTP1B plays a counter-regulatory role in vascular injury-induced
neointima formation. A recent study found that chronic insulin
treatment attenuates PDGF-induced, but not baseline, expression of
PTP1B in differentiated (primary) cultured vascular smooth muscle
cells . The current experiment was designed to test if chronic insulin
treatment suppresses the baseline expression of endogenous PTP1B
in dedifferentiated (passages 5-9) cultured vascular smooth muscle
cells (cells in media and intima of injured arteries), thus promoting
the motogetic effect of IL-6. As shown in (Figure 3), chronic insulin
treatment of vascular smooth muscle cells dose-dependently suppressed
the baseline expression of endogenous PTP1B. The inhibition reached
plateau at the concentration of 20 nM, suggesting that the responses
of differentiated and dedifferentiated smooth muscle cells in response
to chronic insulin treatment are different. Inhibition of endogenous
PTP1B expression in dedifferentiated vascular smooth muscle cells
may play a crucial role in insulin-enhanced vascular injury-induced
restenosis because of the extensive phenotypic similarities between
subcultured aortic smooth muscle cells and the cells in neointima.
|Over expressing wild-type PTP1B attenuates whereas
dominant negative (C215S-PTP1B) potentiates IL-6-
stimulated smooth muscle cells migration
|Our next experiments were designed to test if attenuation of
endogenous PTP1B expression is necessary and/or sufficient to explain
the augmentation of IL-6-stimulated smooth muscle cell migration
caused by chronic insulin treatment. The experiments were performed
by examining the effect of wild-type PTP1B and C215S-PTP1B on IL-
6-stimulated cell migration by transfecting cells with wild-type and
C215S-PTP1B (catalytically essential cystine at 215 is muted to serine)
followed by stimulation with IL-6. As shown in (Figure 4A and 4B),
overexpressing wild-type PTP1B (WT-1B) significantly attenuated the
motogenic effect of IL-6 whereas expressing C215S-PTP1B (CS-1B)
potentiated IL-6-induced cell migration, indicating that downregulation
of endogenous PTP1B may play an important role in insulin-enhanced
motogenic effect of IL-6.
|Over expressing wild-type PTP1B suppresses whereas C215SPTP1B
potentiates IL-6-induced STAT3 phosphorylation
|The aforementioned results suggest that inhibition of PTP1B
expression might contribute to hyperinsulinemia-caused potentiation
of IL-6-induced cell migration. Our next experiments were designed to
test if these effects were mediated through affecting the key element of
IL-6 signaling, STAT3 tyrosine phosphorylation. Cells were transfected
with adenovirus expressing EGFP (control) or wild-type PTP1B or
C215S-PTP1B, followed by the stimulation with IL-6. As shown in
(Figure 5A and 5B) wild-type PTP1B significantly attenuated whereas
C215S-PTP1B enhanced IL-6-induced STAT3 phosphorylation at the
tyrosine 705, suggesting that inhibition of PTP1B expression is the key in
augmentation of IL-6-mediated signaling caused by hyperinsulinemia.
||Figure 1: Chronic insulin treatment potentiates IL-6(20ng/ml)-induced
vascular smooth muscle cell migration. Cells were pretreated with 5nM
of insulin for 24 hours followed by stimulation with 20 ng/ml of interlukin-6 for
24 hours in presence and absence of 5 nM of insulin. The migration distance
before and after IL-6 treatment was measured and expressed as µm/24hrs,
mean+SE. Results are from three independent experiments. Data are analyzed
by using one-way ANOVA followed by post hoc test. *P<0.05, compared
to control, #p<0.05 compared to IL-6 alone.
||Figure 2: Chronic insulin treatment enhances IL-6-induced STAT3 tyrosine
phosphorylation. Cells were treated with serum-free (Figure 2A and 2B)
medium or serum-free medium containing 100 nM (Figure 2C), or 5 nM (Figure
2D) of insulin for 24 hours followed by stimulation with IL-6 for indicated concentrations
(Figure 2A) or 20 ng/ml (Figure 2C and 2D) and indicated times
(Figure 2A) or 30min (Figure 2C and 2D), and lysed with RIPA buffer. p-STAT3
was checked by immunoprecipitation with anti-STAT3 and probed with antiphospho-
STAT3 (Tyr705). Membranes were stripped and reprobed with anti-
STAT3 to serve as a loading control. Upper panels show the representative
Western blot. Graphs show mean ± SE of the ratio of phosphorylated STAT3 to
total STAT3 from three independent experiments. Data were analyzed by using
One-Way ANOVA followed by post hoc test, *P<0.05, **P<0.01, compared to
control and insulin. #P<0.05 compared to IL-6 alone.
||Figure 3: Chronic insulin treatment suppresses baseline expression
of PTP1B in dedifferentiated vascular smooth muscle cells. Cells were
incubated with serum-free medium for 24 hours followed by stimulation
with different concentrations of insulin (5, 10, 20, 50, 100 nM) for 24 hours.
PTP1B protein levels were checked by Western blot directed against PTP1B.
Membranes were reprobed with anti-α-actin to serve as a loading control.
Upper panel shows the representative Western blot. Graph shows mean ± SE
of the ratio of PTP1B to a-actin from three independent experiments. Data
were analyzed by using One-Way ANOVA followed by post hoc test. *P<0.05,
compared to control.
||Figure 4: Wild-type PTP1B attenuates whereas dominant negative
(C215S-PTP1B) potentiates IL-6-stimulated smooth muscle cells migration. Cells were transfected with control virus expressing enhanced green
fluorescent protein (EGFP) or with virus expressing wild-type (WT-1B, Figure
4A)or dominant negative PTP1B (CS-1B, Figure 4B) at multiplicity of infection
values of 10-15 for 24 hours. After viruses were removed, cells were
further incubated for 24 hours to allow time for PTP1B expression. Cells were
then treated with 20 ng/ml of interleukin-6 for 24 hours after wounding. Upper
panels show the representative Western blot indicating the expression levels
of PTP1B. Graphs show the migration distance (mean + SE) from three independent
experiments before and after IL-6 treatment. Data are analyzed by using
one-way ANOVA followed by post hoc test. **P<0.01, compared to control,
##P<0.01 compared to IL-6 alone.
||Figure 5: Wild-type PTP1B suppresses whereas C215S-PTP1B potentiates
IL-6-induced STAT3 phosphorylation. Cells were transfected with adenovirus
expressing enhanced green fluorescent protein (EGFP) or with adenovirus
expressing wild-type (Figure 5A) or C215S PTP1B (Figure 5B) at multiplicity of
infection values of 10-15 for 24 hours. After viruses were removed, cells were
further incubated for 24 hours to allow time for PTP1B expression. Cells were
then stimulated with 20 ng/ml of IL-6 for 30 min. p-STAT3 was checked with
western blot by probing with anti-phospho-STAT3 (Tyr705). The membrane
was stripped and reprobed with anti-STAT3 to serve as a loading control
and incubated with anti-PTP1B to check the overexpression levels. Upper
panels show the representative Western blot indicating the expression levels
of PTP1B. Graphs show mean ± SE of the ratio of phosphorylated STAT3 to
total STAT3 from four independent experiments. Data were analyzed by using
One-Way ANOVA followed by post hoc test. **P<0.01, compared to control,
##P<0.01, compared to IL-6 alone.
||Figure 6: Schematic demonstration of interactions among IL-6, insulin,
and PTP1B. Arrows represent stimulatory whereas blocked lines indicate
inhibitory effects. Question mark signifies the possible mechanism.
|The novel findings of this report are: 1) chronic insulin treatment
potentiated IL-6-induced smooth muscle cell migration and STAT3
tyrosine phosphorylation; 2) chronic insulin dose-dependently suppressed
the baseline expression of endogenous PTP1B in dedifferentiated
vascular smooth muscle cells; 3) over expressing wild-type
PTP1B significantly attenuated, whereas C215S-PTP1B enhanced,
IL-6-induced STAT3 phosphorylation; 4) expressing wild-type PTP1B drastically attenuated, whereas C215S-PTP1B augmented, IL-6-stimulated
smooth muscle cell migration, suggesting that enhanced IL-11-
6 signaling, mediated by down regulation of PTP1B expression, may
contribute to increased risk of vascular restenosis after angioplasty in
patients with hyperinsulinemia.
|It is well established that interactions between inflammatory
cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs),
and extracellular matrix (ECM), and subsequent increased release of
cytokines play pivotal roles in vascular injury-induced restenosis by
promoting smooth muscle cell growth and migration leading to intima
thickening. As a major inflammatory cytokine, IL-6 is one of the early
responders after vascular injury. The involvement of IL-6 in vascular
injury-induced neointima thickening is well established. Elevated
plasma concentration of IL-6 was observed in patients immediately
after angioplasty as well as in injured arteries of animal models [40-42]. Blockade of IL-6-stimulated signaling has produced significant
reduction of vascular injury-induced neointima formation .
However, little is known about the role of IL-6 in insulin-enhanced
neointima formation after vascular injury. Our current data show that
chronic insulin treatment significantly potentiates IL-6-induced smooth
muscle cell migration and STAT3 tyrosine phosphorylation, suggesting
that increased IL-6-induced signaling may play an important role in
augmentation of vascular injury-induced neointima formation caused
|The most recent studies found that chronic insulin treatment of
differentiated vascular smooth muscle cells significantly suppressed
PDGF-stimulated but not the baseline expression of endogenous
PTP1B. Rats with hyperinsulinemia showed attenuation of injury-induced
PTP1B expression compared to those with normal insulinemia
[5,7], suggesting that inhibition of stimulated expression of PTP1B
may play an important role in chronic hyperinsulinemia-enhanced
neointima formation after vascular injury. Our current results show,
for the first time, that insulin dose-dependently suppresses the baseline
expression of endogenous PTP1B in dedifferentiated vascular smooth
muscle cells. We also found that wild-type PTP1B attenuates, whereas
C215S-PTP1B potentiates, IL-6-induced cell migration and STAT3
phosphorylation, suggesting that attenuation of PTP1B expression
in dedifferentiated vascular smooth muscle cells (cells in media and
intima of injured arteries) may serve as a key factor in increased risk of
vascular restenosis in patients with hyperinsulinemia by potentiating
the motogenic effect of IL-6 as well as other growth factors.
|In conclusion, the present findings indicate that inhibition of
baseline expression of PTP1B in dedifferentiated vascular smooth
muscle cells and subsequent potentiation of IL-6-stimulated smooth
muscle migration together may serve as a potential mechanism for
increased risk of vascular restenosis after angioplasty in patients with
|This work was supported by Warner/Fermaturo and ATSU Board of Trustees
|Author thanks the faculty and staff in Department of Pharmacology at A.T. Still
University for their scientific and technical support. We also thank Dr. Theobald and
Mr. Ryan White for their editorial assistance.
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