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(Hypertension. 2001;37:587.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Angiotensin II Induces Migration and Pyk2/Paxillin Phosphorylation of Human Monocytes
From the University of California Los Angeles School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, Los Angeles, Calif (U.K., S.W., S.K., W.A.H., R.E.L.); and the Department of Medicine/Cardiology, Virchowklinikum, Humboldt University Berlin and German Heart Institute Berlin (Germany) (U.K., E.F.).
Correspondence to Ronald E. Law, PhD, UCLA School of Medicine, Division of Endocrinology, Diabetes, and Hypertension, Warren Hall, Second Floor, Suite 24-130, 900 Veteran Ave, Box 957073, Los Angeles, CA 90095. E-mail rlaw{at}med1.medsch.ucla.edu
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Abstract |
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Angiotensin (Ang) II has been shown to enhance the development of atherosclerotic lesions. Migration of monocytes is an early critical step in the atherosclerotic process. To elucidate mechanisms by which Ang II promotes atherogenesis, we investigated its effects on human monocyte migration. Ang II induced migration of human peripheral blood monocytes (HPBM) and human THP-1 monocytes at concentrations between 0.01 and 1 µmol/L, with a 3.6±0.6-fold induction in HPBM and a 4.8±0.9-fold induction in THP-1 cells at 1 µmol/L Ang II (both P<0.01 versus unstimulated cells). Addition of the Ang II receptor type 1 (AT1-R) antagonist losartan (1 to 100 µmol/L) suppressed Ang II–induced migration of HPBM and THP-1 monocytes in a dose-dependent manner, demonstrating an AT1-R–mediated mechanism. Ang II–directed migration was also blocked by the Src kinase inhibitor PP2 (10 µmol/L), by the extracellular-regulated protein kinase (ERK 1/2) inhibitor PD98059 (30 µmol/L), and by the p38-MAPK inhibitor SB203580 (10 µmol/L), indicating that Src, ERK 1/2, and p38 are all involved in Ang II–induced migration of HPBM and human THP-1 monocytes. The proline-rich tyrosine kinase 2 (Pyk2) and paxillin are 2 cytoskeleton-associated proteins involved in cell movement, phosphorylated by Ang II in other cell types, and abundantly expressed in monocytes. Ang II (1 µmol/L) induced Pyk2 and paxillin phosphorylation in human THP-1 monocytes, peaking after 10 minutes for Pyk2 with a 6.7±0.9-fold induction and after 2 minutes for paxillin with a 3.2±0.4-fold induction. Ang II–induced phosphorylation of both proteins was suppressed by losartan and the Src inhibitor PP2, whereas no effect was observed with PD98059 and SB203580. This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R–dependent process, involving signaling through Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins, Pyk2 and paxillin.
Key Words: angiotensin • monocytes • phosphorylation • atherosclerosis
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Introduction |
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Angiotensin (Ang) II is a prominent vasoconstrictor growth factor and has been reported to promote vascular injury and the atherosclerotic process. Pharmacolgical inhibition of the renin-angiotensin system by blockade of ACE has been shown to reduce cardiovascular events in patients with multiple risk factors for atherosclerosis.1 Inhibitors of ACE and Ang II receptor type I (AT1-R)-blockers have been demonstrated to attenuate atherosclerotic lesion formation in a number of animal models.2 3 Recently, Daugherty et al4 have shown that Ang II infusion accelerates atherosclerotic lesions in apolipoprotein E–deficient mice. Ang II was administered at a subpressor dose in these mice, suggesting additional direct proatherogenic actions of this factor. It has been proposed that Ang II may increase the atherogenic process by promoting an inflammatory reaction in multiple cell types of the vessel wall.5 Several proinflammatory actions of Ang II have been described in vascular smooth muscle cells (VSMC) and endothelial cells, including induction of monocyte chemoattractant protein-1 (MCP-1) and stimulation of adhesion molecule expression.6 7 Nevertheless, many aspects of Ang II effects on the atherogenic process remain unclear.
Migration of monocytes into the vascular subendothelium occurs during pathological inflammatory responses and plays a key role in the development of atherosclerosis.8 Transendothelial monocyte migration is a multifactorial mechanism that initially involves adhesion of circulating monocytes to cytokine-regulated adhesion molecules expressed on the surface of the endothelium.9 Adherent monocytes then move through adjacent endothelial cells toward specific chemokines and differentiate into tissue macrophages in the vessel wall.10
Cell movement requires cytoskeletal rearrangement involving phosphorylation of cytoskeleton-associated tyrosine kinases and formation of focal adhesion complexes.11 The proline-rich tyrosine kinase 2 (Pyk2), a member of the p125 focal adhesion kinase (FAK) family, and paxillin are two cytoskeleton-associated proteins involved in cell attachment and movement.12 13 Pyk2 and paxillin colocalize at focal adhesions in response to multiple stimuli.14 Pyk2, also termed cell adhesion kinase-ß, related adhesion focal tyrosine kinase, or calcium-dependent tyrosine kinase and paxillin are abundantly expressed in human monocytes, whereas p125 FAK is expressed at low levels.15 16 Ang II has been shown to stimulate phosphorylation of Pyk2 and paxillin, induce their colocalization, and induce the formation of focal adhesions in VSMC and endothelial cells.13 17
Because transendothelial migration of monocytes is a key event in early inflammation and atherosclerosis and Ang II functions as a potent chemoattractant in other cell types, we hypothesized that Ang II may exert its proatherogenic/proinflammatory effects in part by directly inducing monocyte migration.18 We also studied Ang II effects on signaling pathways promoting phosphorylation of Pyk2 and paxillin and migration of human monocytes.
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Methods |
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Materials
Ang II, PD123319, DMSO, and antibiotics were purchased from Sigma. RPMI 1640 medium with L-glutamine was from GIBCO BRL. Fetal bovine serum (FBS) was purchased from Irvine Scientific. Hybond enhanced chemiluminescence (ECL) nitrocellulose membrane, horseradish peroxidase–linked anti-rabbit and anti-mouse antibody, and ECL Western blotting detection reagents were from Amersham Life Sciences. Cell fixation and staining was performed with the Quik-Diff stain set from DADE. Transwell cell culture chambers (24 well) and polycarbonate membranes (8 µm) were from Becton-Dickinson. Losartan was kindly provided by Merck. The mitogen-activated protein kinase (MAPK) ERK1/ERK2 (Extracellular Regulated Kinase 1/2) inhibitor or MEK (MAPK, ERK Kinase) inhibitor PD98059 was from New England BioLabs. SB203580, PP2, and PP3 were from Calbiochem. Antibodies were purchased from the following vendors: anti-Pyk2 and anti-paxillin from Transduction Laboratories; anti-phosphorylated Pyk2 (pY881) and paxillin (pY31) from Biosource International; antibodies against phosphorylated and total ERK1/ERK2 MAPKs, ATF-2, and p38 from New England BioLabs; anti-Src from Oncogene; and anti-phosphorylated Src (pY416) from Upstate Biotechnology.
Cell Culture
THP-1 cells, a human monocytic leukemia cell line,
were purchased from American Type Culture Collection and human
peripheral blood monocytes (HPBM) from Clonetics. The cells
were cultured in RPMI 1640 medium, containing 10% FBS and
L-glutamine. HPBM were used
for experiments 24 hours after plating.
Migration
Migration experiments were performed in transwell
cell culture chambers as previously
described.19 THP-1 cells and
HPBM were centrifuged, washed in PBS, centrifuged, and
resuspended in RPMI 1640 medium containing 0.2% FBS;
5x104 (THP-1) and
2x105 (HBPM) cells were placed on a
gelatin-coated polycarbonate membrane with 8-µm pores and incubated
at 37°C for 1 hour, allowing the cells to attach. Cells were then
pretreated with the indicated compounds or vehicle (DMSO) for 30
minutes at 37°C. Migration was induced by addition of Ang II to the
lower compartment. After 4 hours (THP-1) and 2 hours (HPBM),
nonmigrating cells were removed with a cotton tip and the membranes
were fixed and stained with Quik-Diff stain set to identify migrated
cells. The number of migrated cells was determined per x200 high-power
field. Experiments were performed in duplicate and were repeated at
least 3 times.
Western Immunoblot
Cells were made quiescent by serum starvation
overnight and were exposed to the compounds or vehicle (DMSO) 30
minutes before stimulation with Ang II. After the indicated time
interval, protein isolation, electrophoresis, and blotting were
performed as previously
described.19 Blots were
incubated with specific antibodies described under Methods.
Immunoreactive bands were visualized with horseradish
peroxidase–conjugated secondary antibodies (1:1000 dilution). The
peroxidase reaction was developed with an ECL detection system
(Amersham Corp). Band intensity was analyzed by
densitometry.
Statistics
ANOVA with paired or unpaired
t tests was performed for
statistical analysis, as appropriate. Values of
P<0.05 were considered to be
statistically significant. Data are expressed as
mean±SEM.
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Results |
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Ang II Induces Migration of Human Monocytes
Ang II stimulated migration of HPBM and THP-1 monocytes at concentrations between 0.01 and 1 µmol/L, with a 3.6±0.6-fold induction in HPBM and a 4.8±0.9-fold induction in THP-1 cells at 1 µmol/L Ang II compared with unstimulated control (HPBM: Ang II 1 µmol/L: 11.9±1.5 cells/high power field, control: 3.3±0.8 cells/high-power field, P<0.05; THP-1: Ang II 1 µmol/L: 9.1±0.5 cells/high-power field, control: 1.9±0.3 cells/high-power field, P<0.01) (Figure 1A).
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Ang II–induced monocyte migration was mediated by signal transduction through the AT1-R because it was dose-dependently abrogated when HPBM and THP-1 cells were treated with the AT1-R antagonist losartan (1 to 100 µmol/L), with a maximal inhibition at 100 µmol/L (100 µmol/L losartan; HPBM: 83.6±0.7% inhibition; THP-1: 91.3±8.6 inhibition, both P<0.01 versus Ang II alone) (Figure 1B). The Ang II receptor type 2 (AT2-R) antagonist PD123319 had no effect (Figure 1B).
Ang II mediates its cellular actions through multiple signaling pathways, among which members of the MAPK family, ERK 1/2, and p38, and the nonreceptor tyrosine kinase c-Src have been shown to play a pivotal role in regulating cell migration.18 20 21 We therefore examined the effect of blocking these pathways on Ang II–induced monocyte migration. The ERK 1/2–MAPK pathway was blocked with the MEK inhibitor PD98059, the p38 MAPK with the specific inhibitor SB203580, and Src signaling was blocked with PP2. A prominent inhibition of migration toward Ang II (1 µmol/L) was observed with the Src inhibitor PP2 in both HBPM and THP-1 cells (PP2 10 µmol/L; HPBM: 79.5±3.2% inhibition; THP-1: 82.9±5.2% inhibition, both P<0.01 versus Ang II alone) (Figure 1B). The inactive analogue PP3 (10 µmol/L) had no significant effect (Figure 1B). Treatment of monocytes with the p38 inhibitor SB203580 (10 µmol/L) led to a 60±4.6% inhibition of migration in HPBM and 71.1±2.25% inhibition in THP-1 monocytes (both P<0.01 versus Ang II alone) (Figure 1B). The MEK inhibitor PD98059 (30 µmol/L) also blocked Ang II–induced monocyte migration by 69±4.6% in HBPM (P<0.01 versus Ang II alone) and 66.7±15.9% in THP-1 cells (P<0.05 versus Ang II alone) (Figure 1B). These results demonstrate that Src, ERK 1/2, and p38 are all involved in Ang II–induced monocyte migration.
Ang II Stimulates
Phosphorylation of Pyk2 and Paxillin in THP-1 Human
Monocytes
To investigate a potential mechanism of Ang II
promigratory actions in human monocytes, we examined its effects on the
phosphorylation of Pyk2 and paxillin, two focal
adhesion–associated proteins involved in cell movement,
phosphorylated by Ang II in other cell types, and
abundantly expressed in monocytes. Ang II (1 µmol/L) induced Pyk2
phosphorylation in human THP-1 monocytes after 1-minute
stimulation, reaching a maximum after 10 minutes with a 6.7±0.9-fold
induction (P<0.05 versus
unstimulated cells)
(Figure 2A and 2B). Paxillin phosphorylation
in THP-1 cells was induced by 3.2±0.4-fold after 2 minutes by Ang II
(1 µmol/L) (P<0.05 versus
unstimulated cells)
(Figure 2A and 2B). Ang II phosphorylated
both focal adhesion proteins in a dose-dependent manner
(Figure 2A).
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Ang II–Induced Phosphorylation
of Pyk2 and Paxillin Is AT1-R and Src Dependent
We next examined whether activation of signaling
pathways involved in Ang II–induced monocyte migration also induce the
phosphorylation of Pyk2 and paxillin
phosphorylation.
Consistent with the results in migration assays, we found that the AT1-R also mediates Ang II stimulation of Pyk2 and paxillin phosphorylation. The AT1-R antagonist losartan (100 µmol/L) potently inhibited the phosphorylation of Pyk2 (69.1±2.6% inhibition, P<0.01 versus Ang II alone [Figure 3A]) and paxillin (60±1% inhibition, P<0.05 versus Ang II alone [Figure 3B]) in THP-1 monocytes. The AT2-R antagonist PD123319 (10 µmol/L) did not affect Ang II–induced Pyk2 and paxillin phosphorylation (Figure 3, A and B).
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Inhibition of Src signaling by PP2 (10 µmol/L) led to a significant reduction of Ang II–induced Pyk2 and paxillin phosphorylation (Pyk2: 66±12.4% inhibition; paxillin: 74±9.5% inhibition, both P<0.05 versus Ang II alone), suggesting that Src is activated upstream of Pyk2 and paxillin (Figure 3, A and B). Treatment with PP3 (10 µmol/L) showed no effect (Figure 3, A and B).
Neither the inhibition of the ERK 1/2–MAPK pathway with PD98059 (30 µmol/L) nor blocking of p38 signaling with SB203580 (10 µmol/L) affected Ang II–stimulated phosphorylation of Pyk2 and paxillin, suggesting that these two pathways are activated downstream or independent of Pyk2 and paxillin phosphorylation in these cells (Figure 3, A and B).
Ang II Induces MAPK ERK1/2 and p38 Activation
in THP-1 Human Monocytes
To further elucidate the signaling events involved in
Ang II–mediated migratory effects in human monocytes, we investigated
the activation of ERK 1/2, p38, and c-Src by Ang II in human THP-1
monocytes.
Activated, phosphorylated ERK 1/2 was investigated by immunoblotting with a phosphospecific ERK1/2 antibody. Ang II induced ERK 1/2 in a time- and dose-dependent manner, with a delayed activation of ERK 1/2 observed after 20 minutes (Figure 4A). Treatment with the MEK inhibitor PD98059 led to a complete inhibition of Ang II–mediated activation of ERK 1/2 and reduced levels of phosphorylated ERK below that detected in unstimulated cells (Figure 4B). Ang II–induced activation of ERK 1/2 in THP-1 human monocytes was also mediated by the AT1-R. The AT1-R antagonist losartan (100 µmol/L) potently attenuated Ang II effects on ERK 1/2, whereas the AT2-R antagonist PD123319 (10 µmol/L) had no effect (Figure 4B).
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Activation of the p38 MAPK signaling pathway leads to phosphorylation and activation of the transcription factor ATF-2.22 To assess the involvement of p38 signaling in Ang II effects in human monocytes, the phosphorylation status of p38 and ATF-2 were examined with phosphospecific antibodies. The maximum of p38 and ATF-2 phosphorylation by Ang II was observed after 5 minutes (Figure 5, A and B). SB203580, a potent p38 inhibitor, abolished Ang II–induced phosphorylation of p38 and ATF-2 (Figure 5, A and B). Losartan (100 µmol/L) also potently attenuated Ang II effects on p38 and ATF-2 activation (Figure 5, A and B).
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Blockade of Src activation by PP2 (10 µmol/L) did not affect Ang II– induced ERK1/2 or p38 activation, indicating that the Src signaling pathway is not involved in Ang II–mediated activation of these pathways in human monocytes (Figure 4B and 5, A and B).
Ang II Induces c-Src Activation in THP-1
Human Monocytes
Because PP2, the potent Src inhibitor,
blocked both Ang II–mediated monocyte migration and Pyk2 and paxillin
phosphorylation, we further investigated the regulation
of this pathway by Ang II in THP-1 human monocytes.
Phosphorylation of c-Src at pY416 within the catalytic domain leads to its activation.23 Ang II (1 µmol/L) induced c-Src phosphorylation at pY416, with a maximum between 1 to 2 minutes (Figure 6A). The Src inhibitor PP2 (10 µmol/L) completely blocked this phosphorylation, whereas the inactive analogue PP3 (10 µmol/L) had no effect (Figure 6B). Ang II induced c-Src phosphorylation through activation of the AT1-R, because losartan (100 µmol/L) abolished Ang II effects (Figure 6B). The AT2-R antagonist PD123319 did not affect Ang II–mediated phosphorylation of c-Src (Figure 6B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R dependent process, involving signaling through c-Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins involved in cell movement, Pyk2 and paxillin.
Ang II has been reported to accelerate the atherosclerotic
process in apolipoprotein E–deficient
mice.4 Because Ang II did not
cause hypertension in that study, additional direct proatherogenic
actions of Ang II were hypothesized, specifically effects on
endothelial cells and
VSMC.5 The function of Ang II
on monocyte/macrophages is poorly understood. Most studies have
focused on the proatherogenic action of Ang II in macrophages
to induce the uptake of oxidized LDL and the further oxidative
modification of LDL in these
cells.24 25 In
monocytes, Ang II has been shown to stimulate the release of
proinflammatory cytokines as interleukin-1ß and tumor
necrosis
factor-
.26 27
Recently, the ACE inhibitor quinapril has been demonstrated
to diminish macrophage recruitment into the vessel wall in an
animal model of accelerated
atherosclerosis.28
The proinflammatory activity of Ang II could result from the induction
of MCP-1 or adhesion molecule expression, as previously observed in
VSMC or endothelial
cells.6 7
Additional mechanisms, however, could further contribute to Ang II
stimulation of monocyte adherence and/or extravasation. In the
present study, we demonstrate that Ang II is a chemoattractant for
human monocytes. Ang II, therefore, may directly induce the
extravasation of inflammatory cells. Nevertheless, this hypothesis
needs to be substantiated in future studies using in vivo and in vitro
models of transendothelial migration. Because recent
studies have shown an increased expression of Ang II and ACE in
coronary atherosclerotic plaques, the chemotactic action of Ang
II on monocytes may play an important role in the atherosclerotic
process.29 30
The underlying mechanism of Ang II–induced migration is poorly understood. A critical step in growth factor–induced migration is the phosphorylation and subsequent colocalization of cytoskeleton-associated proteins involved in cell locomotion.31 In the present study, we show that Ang II rapidly induces paxillin and Pyk2 phosphorylation in human monocytes. Mutation of two phosphorylation sites on paxillin effectively diminished tumor cell migration, indicating the central role of paxillin in cell movement.32 Phosphorylation of Pyk2 has been also recently demonstrated to be required for tumor cell invasion, a process involving cell migration.12 Moreover, Pyk2 translocates to focal adhesions in response to G protein–coupled receptor (GPCR) activation, where it is colocalized with the focal adhesion protein paxillin.14 Because Ang II–directed monocyte migration and Pyk2 and paxillin phosphorylation are mediated by the AT1-R, a GPCR, phosphorylation of Pyk2 and paxillin by Ang II in human monocytes might be an important step in promoting Ang II–promigratory effects.
Ang II has also been demonstrated to induce matrix
metalloproteinase-9 expression in
cardiomyocytes.33
Cell migration requires degradation of basal laminae and
interstitial stroma, processes that involve matrix
metalloproteinases.34
Additional studies are required to determine if Ang II regulates matrix
metalloproteinase (MMP) expression in monocytes. We have recently shown
that Ang II stimulates the expression of the integrin
(v)ß3 in cardiac
fibroblasts, a surface molecule known to be important for cell
migration.35 Regulation of
integrin expression and/or signaling by Ang II may constitute an
additional mechanism for its effects on monocyte migration.
Emerging evidence identifies the Src-kinase pathway as playing a pivotal role in the early events of AT1-R signaling.36 Similar to studies in VSMC, we show that Ang II rapidly induces c-Src phosphorylation/activation in human monocytes through the AT1-R.37 Blocking this signaling pathway either by treatment with an Src inhibitor or an AT1-R antagonist leads to complete inhibition of Ang II–directed migration in these cells. These findings are consistent with studies in fibroblasts from Src-deficient mice, which exhibit impaired locomotion.20 Furthermore, c-Src has been shown to associate with Pyk2 on Ang II stimulation, and its activation is required for Ang II–induced paxillin phosphorylation and subsequent cytoskeletal reorganization.38 39 Src inhibition also prevents Ang II–induced Pyk2 and paxillin phosphorylation in monocytes, which may interfere with cytoskeletal reorganization required for monocyte movement.
Our group and others have demonstrated that activation of the ERK 1/2 and p38 MAPK pathways is involved in Ang II signaling and stimulation of migration.18 40 Ang II–induced monocyte migration appears to be, at least in part, regulated by these two pathways. Phosphorylation of Pyk2 and paxillin in response to Ang II, however, is independent of ERK or p38 activation. Dominant negative mutants of Pyk2 significantly attenuate Ang II–induced ERK activity.41 In addition, overexpression of Pyk2 has been shown to activate p38.42 Together, these studies suggest that activation of ERK 1/2 and p38 occurs downstream or independent of Pyk2.
This study demonstrates that Src activation is not involved in Ang II–induced activation of ERK 1/2 in monocytes. This is consistent with reports in cardiomyocytes in which ERK 1/2 activation by Ang II is also independent of c-Src.43 In contrast, studies in VSMC have shown that ERK 1/2 activation by Ang II is dependent on c-Src.44 Although the relation among Ang II, c-Src, and p38 is poorly understood, activation of p38 by other stimuli has also been shown to be dependent on Src activity.45 We observed that activation of p38 by Ang II does not involve c-Src. Consistent with that finding are studies in VSMC showing that Src does not mediate p38 activity stimulated by reactive oxygen species involved in Ang II signaling.46 In combination with our data, these studies suggest that c-Src and the MAPKs ERK and p38 may transduce migratory signals through distinct pathways in monocytes. We recently demonstrated that ERK 1/2 activation is involved in PMA-induced MMP-9 expression in human monocytes, suggesting that this pathway may affect MMP-dependent invasion, a process also required for a migratory response.47 Nevertheless, future studies are required to precisely define which components of the cell migration machinery are regulated by different signaling pathways activated through the AT1-R.
Conclusions
This study demonstrates a novel proatherogenic action
of Ang II on monocytes by inducing their migration. Inhibition of this
action by ACE inhibitors or AT1-receptor
antagonists, therefore, may prevent or retard the
atherosclerotic process in
humans.
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Acknowledgments |
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This study was supported by a National Institutes of Health Grant to Dr Hsueh (HL-58328-03). Dr Kintscher was supported by a research fellowship by the Gonda (Goldschmied) Diabetes Center, University of California, Los Angeles. Dr Wakino was supported by a fellowship by the Mary K. Iacocca Foundation.
Received October 24, 2000; first decision December 4, 2000; accepted December 18, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–153.
2.
Chobanian AV,
Haudenschild CC, Nickerson C, Drago R. Antiatherogenic effect of
captopril in the Watanabe heritable hyperlipidemic
rabbit. Hypertension. 1990;15:327–331.
3.
Hayek T, Attias J,
Coleman R, Brodsky S, Smith J, Breslow JL, Keidar S. The
angiotensin-converting enzyme inhibitor,
fosinopril, and the angiotensin II receptor
antagonist, losartan, inhibit LDL oxidation and
attenuate atherosclerosis independent of lowering blood
pressure in apolipoprotein E deficient mice.
Cardiovasc Res. 1999;44:579–587.
4. Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000;105:1605–1612.[Medline] [Order article via Infotrieve]
5. Berk BC, Haendeler J, Sottile J. Angiotensin II, atherosclerosis, and aortic aneurysms. J Clin Invest. 2000;105:1525–1526.[Medline] [Order article via Infotrieve]
6.
Chen XL, Tummala
PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II
induces monocyte chemoattractant protein-1 gene expression in rat
vascular smooth muscle cells. Circ
Res. 1998;83:952–959.
7.
Grafe M,
Auch-Schwelk W, Zakrzewicz A, Regitz-Zagrosek V, Bartsch P, Graf K,
Loebe M, Gaehtgens P, Fleck E, Angiotensin II-induced
leukocyte adhesion on human coronary
endothelial cells is mediated by E-selectin.
Circ Res. 1997;81:804–811.
8.
Ross R.
Atherosclerosis: an inflammatory disease.
N Engl J Med. 1999;340:115–126.
9. Bevilacqua MP, Nelson RM, Mannori G, Cecconi O. Endothelial-leukocyte adhesion molecules in human disease. Annu Rev Med. 1994;45:361–378.[Medline] [Order article via Infotrieve]
10. Adams DH, Shaw S. Leucocyte-endothelial interactions and regulation of leucocyte migration. Lancet. 1994;343:831–836.[Medline] [Order article via Infotrieve]
11. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature. 1995;377:539–544.[Medline] [Order article via Infotrieve]
12. Zrihan-Licht S, Fu Y, Settleman J, Schinkmann K, Shaw L, Keydar I, Avraham S, Avraham H. RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion. Oncogene. 2000;19:1318–1328.[Medline] [Order article via Infotrieve]
13. Turner CE. Paxillin. Int J Biochem Cell Biol. 1998;30:955–959.[Medline] [Order article via Infotrieve]
14.
Litvak V, Tian D,
Shaul YD, Lev S. Targeting of PYK2 to focal adhesions as a cellular
mechanism for convergence between integrins and G protein-coupled
receptor signaling cascades. J Biol
Chem. 2000;275:32736–32746.
15.
Li X, Hunter D,
Morris J, Haskill JS, Earp HS. A calcium-dependent tyrosine kinase
splice variant in human monocytes: activation by a two-stage process
involving adherence and a subsequent intracellular signal.
J Biol Chem. 1998;273:9361–9364.
16.
Williams LM,
Ridley AJ. Lipopolysaccharide induces actin reorganization and
tyrosine phosphorylation of Pyk2 and paxillin in
monocytes and macrophages. J
Immunol. 2000;164:2028–2036.
17.
Tang H, Zhao ZJ,
Landon EJ, Inagami T. Regulation of calcium-sensitive tyrosine kinase
Pyk2 by angiotensin II in endothelial
cells: roles of Yes tyrosine kinase and tyrosine phosphatase SHP-2.
J Biol Chem. 2000;275:8389–8396.
18.
Xi XP, Graf K,
Goetze S, Fleck E, Hsueh WA, Law RE. Central role of the MAPK pathway
in ang II-mediated DNA synthesis and migration in rat vascular smooth
muscle cells. Arterioscler Thromb Vasc
Biol. 1999;19:73–82.
19. Goetze S, Xi XP, Kawano H, Gotlibowski T, Fleck E, Hsueh WA, Law RE. PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. J Cardiovasc Pharmacol. 1999;33:798–806.[Medline] [Order article via Infotrieve]
20. Hall CL, Lange LA, Prober DA, Zhang S, Turley EA. pp60(c-src) is required for cell locomotion regulated by the hyaluronanreceptor RHAMM. Oncogene. 1996;13:2213–2224.[Medline] [Order article via Infotrieve]
21.
Hedges JC,
Dechert MA, Yamboliev IA, Martin JL, Hickey E, Weber LA, Gerthoffer WT.
A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration.
J Biol Chem. 1999;274:24211–24219.
22.
Jiang Y, Chen C,
Li Z, Guo W, Gegner JA, Lin S, Han J. Characterization of the
structure and function of a new mitogen-activated protein
kinase (p38beta). J Biol
Chem. 1996;271:17920–17926.
23. Kmiecik TE, Shalloway D. Activation and suppression of pp60c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell. 1987;49:65–73.[Medline] [Order article via Infotrieve]
24. Keidar S. Angiotensin, LDL peroxidation and atherosclerosis. Life Sci. 1998;63:1–11.[Medline] [Order article via Infotrieve]
25.
Scheidegger KJ,
Butler S, Witztum JL. Angiotensin II increases
macrophage-mediated modification of low density lipoprotein via
a lipoxygenase-dependent pathway.
J Biol Chem. 1997;272:21609–21615.
26.
Dorffel Y, Latsch
C, Stuhlmuller B, Schreiber S, Scholze S, Burmester GR, Scholze J.
Preactivated peripheral blood monocytes in patients
with essential hypertension.
Hypertension. 1999;34:113–117.
27. Hahn AW, Jonas U, Buhler FR, Resink TJ. Activation of human peripheral monocytes by angiotensin II. FEBS Lett. 1994;347:178–180.[Medline] [Order article via Infotrieve]
28.
Hernandez-Presa
M, Bustos C, Ortego M, Tunon J, Renedo G, Ruiz-Ortega M, Egido J.
Angiotensin-converting enzyme inhibition prevents
arterial nuclear factor-kappa B activation, monocyte
chemoattractant protein-1 expression, and macrophage
infiltration in a rabbit model of early accelerated
atherosclerosis.
Circulation. 1997;95:1532–1541.
29.
Diet F, Pratt RE,
Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of
tissue ACE in human atherosclerotic coronary artery disease.
Circulation. 1996;94:2756–2767.
30.
Schieffer B,
Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M,
Nussberger J, Harringer W, Drexler H. Expression of
angiotensin II and interleukin 6 in human coronary
atherosclerotic plaques: potential implications for inflammation and
plaque instability.
Circulation. 2000;101:1372–1378.
31. Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol. 2000;2:249–256.[Medline] [Order article via Infotrieve]
32.
Petit V, Boyer B,
Lentz D, Turner CE, Thiery JP, Valles AM.
Phosphorylation of tyrosine residues 31 and 118 on
paxillin regulates cell migration through an association with CRK in
NBT-II cells. J Cell Biol. 2000;148:957–970.
33. Rouet-Benzineb P, Gontero B, Dreyfus P, Lafuma C. Angiotensin II induces nuclear factor-kappa B activation in cultured neonatal rat cardiomyocytes through protein kinase C signaling pathway. J Mol Cell Cardiol. 2000;32:1767–1778.[Medline] [Order article via Infotrieve]
34.
Westermarck J,
Kahari VM. Regulation of matrix metalloproteinase expression in tumor
invasion. FASEB J. 1999;13:781–792.
35.
Graf K, Neuss M,
Stawowy P, Hsueh WA, Fleck E, Law RE. Angiotensin II and
alpha(v)beta(3) integrin expression in rat neonatal cardiac
fibroblasts. Hypertension. 2000;35:978–984.
36. Berk BC. Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. J Am Soc Nephrol. 1999;10:S62–S68.
37.
Ishida M, Marrero
MB, Schieffer B, Ishida T, Bernstein KE, Berk BC.
Angiotensin II activates pp60c-src in vascular
smooth muscle cells. Circ Res. 1995;77:1053–1059.
38. Ishida T, Ishida M, Suero J, Takahashi M, Berk BC. Agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in vascular smooth muscle cells require c-Src. J Clin Invest. 1999;103:789–797.[Medline] [Order article via Infotrieve]
39.
Eguchi S, Iwasaki
H, Inagami T, Numaguchi K, Yamakawa T, Motley ED, Owada KM, Marumo F,
Hirata Y. Involvement of PYK2 in angiotensin II signaling
of vascular smooth muscle cells.
Hypertension. 1999;33:201–206.
40.
Ushio-Fukai M,
Alexander RW, Akers M, Griendling KK. p38 Mitogen-activated
protein kinase is a critical component of the redox-sensitive signaling
pathways activated by angiotensin II: role in
vascular smooth muscle cell hypertrophy.
J Biol Chem. 1998;273:15022–15029.
41.
Murasawa S, Mori
Y, Nozawa Y, Masaki H, Maruyama K, Tsutsumi Y, Moriguchi Y, Shibasaki
Y, Tanaka Y, Iwasaka T, Inada M, Matsubara H. Role of calcium-sensitive
tyrosine kinase Pyk2/CAKbeta/RAFTK in angiotensin II
induced Ras/ERK signaling.
Hypertension. 1998;32:668–675.
42.
Pandey P, Avraham
S, Kumar S, Nakazawa A, Place A, Ghanem L, Rana A, Kumar V, Majumder
PK, Avraham H, Davis RJ, Kharbanda S. Activation of p38
mitogen-activated protein kinase by PYK2/related adhesion focal
tyrosine kinase-dependent mechanism.
J Biol Chem. 1999;274:10140–10144.
43.
Zou Y, Komuro I,
Yamazaki T, Aikawa R, Kudoh S, Shiojima I, Hiroi Y, Mizuno T, Yazaki Y.
Protein kinase C, but not tyrosine kinases or Ras, plays a critical
role in angiotensin II-induced activation of Raf-1 kinase
and extracellular signal-regulated protein kinases in cardiac myocytes.
J Biol Chem. 1996;271:33592–33597.
44.
Ishida M, Ishida
T, Thomas SM, Berk BC. Activation of extracellular signal-regulated
kinases (ERK1/2) by angiotensin II is dependent on c-Src in
vascular smooth muscle cells. Circ
Res. 1998;82:7–12.
45.
Versteeg HH,
Hoedemaeker I, Diks SH, Stam JC, Spaargaren M, van Bergen En Henegouwen
PM, van Deventer SJ, Peppelenbosch MP. Factor VIIa/tissue
factor-induced signaling via activation of Src-like kinases,
phosphatidylinositol 3-kinase, and Rac.
J Biol Chem. 2000;275:28750–28756.
46.
Yoshizumi M, Abe
J, Haendeler J, Huang Q, Berk BC. Src and Cas mediate JNK activation
but not ERK1/2 and p38 kinases by reactive oxygen species.
J Biol Chem. 2000;275:11706–11712.
47. Kintscher U, Goetze S, Wakino S, Kim S, Nagpal S, Chandraratna RA, Graf K, Fleck E, Hsueh WA, Law RE. Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes. Eur J Pharmacol. 2000;401:259–270.[Medline] [Order article via Infotrieve]
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