(Circulation. 1999;100:1223-1229.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Angiotensin II Induces Vascular Cell Adhesion Molecule-1 Expression In Rat Vasculature
A Potential Link Between the Renin-Angiotensin System and Atherosclerosis
From the Division of Cardiology (P.E.T., X.-L.C., R.W.A., D.G.H., R.M.M.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; AtheroGenics Inc. (C.L.S., C.P.H., R.M.M.), Norcross, Ga; and Division of Cardiology (J.B.L.), Rigshospitalet, Copenhagen, Denmark.
Correspondence to Russell M. Medford MD, PhD, AtheroGenics Inc., 8995 Westside Parkway, Alpharetta, GA 30004. E-mail rmedford{at}atherogenics.com
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Abstract |
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Background—Cardiovascular ischemic events may occur more frequently in hypertensive patients with activated renin-angiotensin systems. We tested the hypothesis that angiotensin II (Ang II) may contribute to atherosclerosis by increasing expression of vascular inflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1).
Methods and Results—Rats infused with norepinephrine
or Ang II for 6 days developed similar hypertensive responses, but only
Ang II-treated rats exhibited significant increases in aortic VCAM-1
protein and mRNA expression. Oral losartan treatment (50
mg · kg-1 · d-1) inhibited Ang
II-induced hypertension and aortic VCAM-1 mRNA expression. Ang II
treatment significantly increased VCAM-1 mRNA expression in cultured
rat aortic smooth muscle cells (RASMCs). Ang II also induced nuclear
NF-
B-like binding activity and transactivated an
NF-B–driven VCAM-1 promoter. Losartan and proteasome
inhibitors blocked Ang II-induced NF-B activation and
VCAM-1 mRNA accumulation. IB-
overexpression in RASMCs inhibited
Ang II-induced VCAM-1 promoter transactivation.
Conclusions—Ang II may contribute to atherogenesis by activation
of VCAM-1 through proteasome dependent, NF-B-like transcriptional
mechanisms.
Key Words: angiotensin • hypertension • VCAM-1 • NF-B
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The molecular mechanisms underlying hypertension as a risk factor for atherosclerosis are poorly understood.1 2 Atherosclerosis may be characterized as an inflammatory disease involving the upregulation of mononuclear leukocyte recruiting mechanisms in response to oxidative stress in the vessel wall.1 Neointimal monocyte infiltration is a key initial step in atheroma formation.3 Monocyte recruitment is mediated, in part, by vascular cell adhesion molecule-1 (VCAM-1), a cell surface protein expressed by endothelial and smooth muscle cells. VCAM-1 is induced by a variety of inflammatory signals, and it mediates monocyte adherence via interaction with the integrin counter-receptor very late antigen-4.4 5 VCAM-1 is observed in endothelium and smooth muscle of early atherosclerotic lesions.6 7 8 VCAM-1 gene expression is activated through an oxidation-reduction sensitive mechanism that involves activation of the transcription factor NF-
B.9 10 Epidemiological studies suggest that hypertensive patients with activated renin-angiotensin systems have a higher risk for myocardial infarction than other forms of hypertension.11 12 13 Treatment of patients with left ventricular dysfunction with angiotensin converting enzyme (ACE) inhibitors reduces recurrent myocardial infarctions and mortality.14 15 These data suggest a potential role of the renin-angiotensin system in contributing to the atherosclerotic process.
Angiotensin II (Ang II), an important component of the
renin-angiotensin system, can induce oxidative stress in
the vasculature via generation of oxygen-free radicals.16
Superoxide anion is generated by membrane-bound NADH/NADPH oxidase in
aortas from rats made hypertensive with Ang II but not
norepinephrine.17 Therefore, oxidative
signaling is a feature shared by Ang II's effects on cellular
metabolism and regulation of VCAM-1 gene expression. In
this study, we found that Ang II directly stimulates VCAM-1 mRNA and
protein expression in aortic tissue of rats. This induction appears to
be mediated via the AT1 receptor. In cultured rat aortic smooth muscle
cells (RASMCs), Ang II induces VCAM-1 gene expression and NF-B
activation. Our data suggest that Ang II may contribute to the
atherosclerotic process by inducing the expression of inflammatory
genes, such as VCAM-1, through NF-B-like transcriptional
mechanisms.
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Methods |
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Materials
All preparations of Ang II (Sigma and Calbiochem) tested negative for endotoxin by Limulus amoebocyte lysate assay (ICN Pharmaceuticals Inc.). Other materials included losartan (a gift from Dr Ronald Smith, Du Pont Pharmaceuticals and Merck, Inc.), lactacystin (Dr E.J. Corey, Harvard University), PD123319 (Research Biochemicals International), N-Ac-leu-leu-norleucinal (LLnL; Calbiochem), antibodies to p65 and c-fos (Santa Cruz Biotechnology Inc., Santa Cruz, Calif), and I
B- expression vector
(a gift from Dr Dean Ballard, Vanderbilt University).
Animal Studies
Chronic arterial catheters were placed into male
Sprague-Dawley rats (250 to 300 g) as previously
described.18 Osmotic minipumps were implanted
subcutaneously to deliver drugs at a constant infusion rate as
previously described17 : Ang II (0.7 mg ·
kg-1 · d-1),
norepinephrine (2.8 mg ·
kg-1 · d-1) or
vehicle (0.9% NaCl). Arterial pressures were measured
while rats were conscious.18 After lethal pentobarbital
injection but before death, 2500 U intracardiac heparin was given.
Aortic arches and thoracoabdominal aortas were collected for
immunohistochemistry and Northern analysis, respectively.
Immunohistochemistry
Immunohistochemistry was performed as previously
described.19 Antibodies were used at the following
dilutions: goat anti-rat VCAM-1 (Berkeley Antibody Company, Richmond,
Calif) and nonimmune goat IgG (Sigma, St. Louis, Mo): 1:200 goat
anti-human Von Willebrand's Factor (VWF, which cross-reacts with Rat
VWF; Incstar, Stillwater, Minn): 1:1000. Biotinylated rabbit anti-goat
secondary antibody (Dako, Carpinteria, Calif): 1:2000. All slide
micrographs were digitized and images developed with Adobe Photoshop in
uniform manner.
Cell Culture
RASMCs were grown in DMEM supplemented with 10% FBS, 2
mmol/L L-glutamine, penicillin (100 U/mL) and streptomycin (100 mg/mL).
Experiments were conducted on cells at passages 5 to 15. Confluent
RASMCs were quiesced in DMEM with 0.1% FBS for 48 hours. Cell cultures
were incubated at 37°C in 5% C02-95%
humidified air.
Northern Analysis
Northern analysis was performed as previously
described.20 Hybridizations with a 1.2-kb EcoR
I-Xho I fragment of murine VCAM-1 cDNA were performed at
60°C for 2 hours in QuickHyb solution (StrataGene). Filters were
washed with a final stringency of 0.2xSSC at 55°C for 30 minutes.
Autoradiography was performed with a PhosphorImager
445sI (Molecular Dynamics).
Electrophoretic Mobility Shift Analysis (EMSA)
Nuclear extracts from RASMCs were prepared as described
previously.21 The oligonucleotide
containing the L-R NF-B consensus sequence (GGGATTTCC) was
labeled and EMSA performed as previously described.20 21
Specificity of NF-B-like binding was confirmed by incubation with
100-fold molar excess of unlabelled competitor probe and mutated probe.
These data were further confirmed by using an
oligonucleotide containing the HIV LTR canonical B
sequence: (GTTACAAGGGACTTTCCGCTGGGG-ACTTTCCAGGGAG).
Analysis of VCAM-1 Promoter Activation
RASMCs were grown to 60% to 80% confluence in 60
mm2 tissue culture plates and transfected with 5
µg of p85VCAM-CAT by calcium phosphate coprecipitation as described
previously.20 p85VCAM-CAT is a chimeric reporter gene
containing coordinates -85 to +12 of the human VCAM-1 promoter linked
to a chloramphenicol acetyl transferase reporter (CAT) gene. With
cotransfection studies, RASMCs were cotransfected with p85VCAM-CAT (5
µg/dish) plus either empty vector (5 µg/dish) or IB-
expression vector22 (5 µg/dish). After 24 hours, the
cells underwent quiescence in medium containing 0.1% FBS for 24 hours.
RASMCs were then treated with Ang II for 16 hours. CAT activities were
determined as previously described.20 Acetylated
and unacetylated forms of chloramphicol were separated by
thin-layer chromatography and imaged by the
PhosphorImager 445Si.
Statistical Analysis
VCAM-1 mRNA accumulation was quantified via densitometry of
bands on Northern analyses. Measurements were expressed as
fraction of control levels and compared among groups using an unpaired
Student's t test with Bonferroni protection. Mean aortic
pressure measurements were also compared using an unpaired Student's
t test.
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Results |
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Effects of Ang II and Norepinephrine on Blood Pressure and Aortic VCAM-1 mRNA Accumulation
Rats treated with Ang II (0.7 mg · kg-1 · d-1) or norepinephrine (2.8 mg · kg-1 · d-1) developed increased mean arterial pressures from 100 to 182 and 185 mm Hg, respectively, 6 days after infusion (Figure 1C
). Northern analysis of whole
aortic RNA showed a marked increase in VCAM-1 (2.8±0.6 x
control) mRNA levels in Ang II treated rats (n=6) when compared with
controls (n=6, P<0.05; Figure 1A and 1B).
Norepinephrine-treated rats exhibited no significant
increase (1.3±0.1 x control) in aortic VCAM-1 mRNA levels (n=4,
P=NS; Figure 1A and 1B).
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Ang II Infusion Induces VCAM-1 Expression in Rat Aortas
Rats treated with Ang II for 6 days demonstrated a marked increase
in VCAM-1 protein expression localized predominantly to the adventitia
(Figure 2A, arrow) and
endothelium (arrowhead). A low level of increased
expression was detected in the media. The specificity of VCAM-1
localization was demonstrated by the lack of staining in a serial
section with nonimmune goat IgG (Figure 2B). No VCAM-1 protein
immunoreactivity was detected in a sham-treated rat aorta (Figure 2C). The lack of VCAM-1 staining in the sham-treated control was
not due to lack of intact endothelium as evidenced by
robust endothelial staining of a serial section with an
antibody to VWF (Figure 2D; arrowhead).
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Ang II-Induced VCAM-1 Gene Expression is Mediated By the AT1
Receptor
Rats were treated with the AT1 receptor antagonist
losartan 2 days before Ang II infusion and throughout the 6
days of Ang II treatment. Oral losartan treatment (50 mg
· kg-1 · d-1)
inhibited Ang II-induced hypertension (MAP= 108 mm Hg, n=4,
Figure 3, top) and aortic VCAM-1 mRNA
expression (P<0.05, Figure 3, bottom). Lower dose
losartan treatment (25 mg ·
kg-1 · d-1) also
blocked Ang II-induced hypertensive response (MAP=107 mm Hg, n=6,
Figure 3, top) but had no effect on Ang II-induced VCAM-1 gene
expression (P=NS, n=4). Rats infused with the AT2 receptor
antagonist PD123319 (30 µg ·
kg-1 · min-1) for
6 days increased aortic VCAM-1 mRNA levels. PD123319 treatment had no
effects on Ang II induced aortic VCAM-1 mRNA accumulation (data not
shown).
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Ang II Induces VCAM-1 mRNA Accumulation Via the ATI Receptor in
Cultured RASMCs
Although our in vivo study shows that Ang II-induced VCAM-1
expression occurs predominantly in the endothelium and
the adventitia, a low level of increased expression occurred in smooth
muscle cells of the media. Cultured, passaged
endothelial cells do not express AT1 receptors in a
stable manner and did not express VCAM-1 in response to Ang II (data
not shown). We therefore used RASMCs to study the signaling mechanisms
of Ang II-induced VCAM-1 gene expression.
RASMCs were treated with or without Ang II for 6 hours. There was some
basal VCAM-1 mRNA expression in unstimulated RASMCs (Figure 4A). Treatment with 1 nmol/L Ang II
caused a 1.9-fold increase in VCAM-1 mRNA expression. Maximal induction
occurred at 10 nmol/L. Ang II-induced VCAM-1 mRNA accumulation appeared
at 2 hours, peaked at 4 to 8 hours, and disappeared at 24 hours (Figure 4B).
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RASMCs were pretreated for 15 minutes with losartan (10
µmol/L), which blocked the increase in VCAM-1 mRNA caused by Ang II
(100 nmol/L, Figure 4C
). Losartan had no effect on
TNF-induced VCAM-1 expression (data not shown). The AT2 receptor
antagonist PD123319 had no effect on basal or Ang
II-induced VCAM-1 mRNA accumulation (data not shown).
LLnL and Lactacystin Inhibit Ang II-Induced VCAM-1 mRNA
Accumulation in RASMCs
Nuclear translocation of NF-B in endothelial
cells is dependent on its dissociation from and degradation of
IB- via the ubiquitin-proteasome pathway.23 24
RASMCs were treated with the proteasome inhibitors LLnL or
lactacystin for 1 hour before and throughout a 6-hour exposure to Ang
II. Ang II-induced VCAM-1 mRNA accumulation was abolished by
pretreatment with both LLnL and lactacystin (Figure 5).
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Ang II Induces NF-B Binding Activities in RASMCs Through an AT1
Receptor Mediated Mechanism
Nuclear extracts were prepared from RASMCs after 1-hour exposure
to Ang II (10 and 100 nmol/L); EMSA for NF-B-like binding activity
to the VCAM-1 NF-B consensus sequence elements, L-R, was
performed. Ang II treatment significantly increased NF-B binding
activity compared with the low basal activity in nonstimulated cells
(Figure 6A). The specificity of
NF-B-like binding activity was confirmed by competition with either
100-fold molar excess of unlabelled probe or mutated probe.
Furthermore, the NF-B band is specifically bound and disappears in
the presence of antibody to p65 but not antibody to c-fos
(Figure 6A). Similar results were obtained using an HIV LTR
canonical B sequence (data not shown). Losartan (10
µmol/L) blocked Ang II-induced (100 nmol/L) nuclear NF-B binding
activity (Figure 6B).
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IB- Overexpression Inhibits Ang II-induced VCAM-1
Promoter Transactivation
RASMCs were cotransfected with 5 µg/dish p85VCAM-1-CAT, whose
activation is dependent on a L-R NF-B consensus
sequence,25 plus either an empty vector (5 µg/dish) or
IB- expression vector (5 µg/dish). Ang II treatment
significantly increased p85VCAM-CAT promoter activity (Figure 7). Cotransfection with IB-
expression vector inhibited this activation. RASMCs transfected with
the constitutional SV2 promoter demonstrated no
increase in promoter activity with Ang II treatment (100 nmol/L, data
not shown).
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Proteasome Inhibitors Block Ang II-induced NF-B
Activation
RASMCs were treated with LLnL or lactacystin for 1 hour before and
throughout 1-hour exposure to Ang II. Ang II-induced nuclear NF-B
binding activity was abolished by pretreatment with LLnL or lactacystin
(Figure 8).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study we established that Ang II-mediated experimental hypertension in rats is associated with increased expression of aortic VCAM-1, an inducible adhesion protein associated with inflammatory events in atherosclerosis. Whether hypertension per se is sufficient to activate vascular inflammatory responses remains an important unresolved question. The present study showed that for similar degrees of hypertension, Ang II induced much greater vascular VCAM-1 gene expression than norepinephrine. These results suggest that although hypertension alone could play some role in upregulating VCAM-1 expression, it is not sufficient to fully activate vascular VCAM-1 expression. Several studies corroborate our data that Ang II influences vascular pathophysiology in addition to its pressor effects. Rats made hypertensive by Ang II, but not norepinephrine, infusion exhibit an increase in aortic superoxide generation via activation of membrane-bound NADH/NADPH oxidase.17 Similarly, Ang II stimulates NADH/NADPH oxidase in vascular smooth muscle cells.16 These studies, in concert with our data, suggest that Ang II and not hypertension alone may initiate oxidative signaling mechanisms; these mechanisms in turn activate redox-sensitive transcription factors such as NF-
B26 27 and upregulate the expression of NF-B
driven genes such as VCAM-1.
Our data suggests that the AT1 receptor mediates Ang II-induced VCAM-1
gene expression. Losartan treatment at 25 mg ·
kg-1 · d-1
inhibited Ang II-induced hypertension, but not Ang II-mediated VCAM-1
expression. Higher doses (50 mg ·
kg-1 · d-1) are
required to inhibit Ang II-induced VCAM-1 mRNA expression in rat
aortas. Therefore, Ang II induces VCAM-1 gene expression through a
mechanism that is distinct from its role in the development of
hypertension. A potential explanation for this finding is that the AT1
receptor may have a higher threshold for inducing signaling mechanisms
for vasoconstriction compared with mechanisms for NF-B activation.
Alternatively, Ang II may use other types of receptors to
activate VCAM-1 gene expression. We explored the possibility of
Ang II cleaved products such as angiotensin IV in
mediating the upregulation of VCAM-1 expression, perhaps via other
receptors, but found that RASMCs treated with angiotensin
IV did not increase VCAM-1 mRNA levels; furthermore, the Ang IV
receptor antagonist divalinal-Ang IV28 did not
inhibit Ang II-induced VCAM-1 mRNA accumulation in RASMCs (data not
shown). PD123319 treatment did not effect basal or Ang
II-induced VCAM-1 expression in RASMCs, suggesting that the AT2
receptor may not be involved in Ang II-induced VCAM-1 mRNA
accumulation. Interestingly, PD123319 increased aortic VCAM-1 mRNA
levels in the whole animal study. The mechanism for this finding is
unclear, but it is possible that AT2 receptor blockade in vivo may
upregulate AT1 receptor-mediated signaling. However, there is no
published data to support this notion, and further exploring this
mechanism is beyond the scope of this study.
To explore the mechanisms of Ang II-induced VCAM-1 gene expression, we initially used cultured endothelial cells and found that they did not express the VCAM-1 gene in response to Ang II because they lose their ability to express AT-1 receptors in early passages (data not shown). This may explain the differences in published data regarding Ang II actions in endothelial cells. Grafe and coworkers reported that Ang II induces E-selectin gene expression in, and leukocyte adhesion to, human coronary endothelial cells. However, Ang II did not induce VCAM-1 expression in this study.29 Kim et al reported that Ang II induces monocyte adherence to endothelial cells without inducing VCAM-1, ICAM-1, or E-selectin gene expression.30 Because Ang II was unable to stimulate VCAM-1 gene expression in cultured endothelial cells, we used RASMCs, which express the AT-1 receptor in a stable manner through many passages, to study the mechanisms of VCAM-1 gene activation by Ang II.
We demonstrated that Ang II induces VCAM-1 gene expression at
physiological concentrations (1 nmol/L) in RASMCs.
Peak responses occurred at concentrations of 10 and 100 nmol/L, which
are similar to those in other reports of Ang II
actions.31 32 33 In endothelial and vascular
smooth muscle cells, cytokine mediated VCAM-1 gene expression
occurs through NF-B mediated transcriptional
mechanisms.9 10 The VCAM-1 promoter contains B-like
elements that are essential for its activation by
cytokines.25 34 We demonstrated that Ang II
activates nuclear NF-B-like DNA binding activity that is
functional in its ability to transactivate B containing
promoters. Li and coworkers reported that Ang II can activate
NF-B and stimulate angiotensinogen gene expression
through NF-B-mediated transcriptional mechanisms in rat
hepatocytes.35 Consistent with this
mechanism, we found that Ang II-induced VCAM-1 mRNA accumulation is
blocked by inhibitors of the proteasome, an intracellular
multicatalytic proteinase complex that degrades ubiquitinated IB-
and enables nuclear translocation of NF-B.23 24
Furthermore, overexpression of IB- inhibited Ang II-induced
VCAM-1 promoter transactivation in RASMCs. These data suggest a
potentially significant role of a proteasome sensitive, NF-B-like
transcriptional mechanism in Ang II mediated VCAM-1 gene expression in
vascular smooth muscle cells.
Numerous studies suggest the importance of the renin-angiotensin system in atherogenesis. Hypertensive patients with high renin profiles and the deletion polymorphism DD ACE genotype, which is associated with higher levels of plasma ACE,36 may have a higher risk for myocardial infarction than those with low renin profiles.11 12 13 Treatment of patients with ACE inhibitors after suffering a myocardial infarction decreases the number of recurrent myocardial infarctions and overall mortality.14 15 37 These reductions in ischemic events are not fully explained by the drugs' hemodynamic effects.37 ACE inhibitors reduce atherosclerotic lesions in several animal models including Watanabe hyperlipidemic rabbits,38 cholesterol-fed monkeys,39 and mice.40 Several studies suggest a direct role of Ang II in atherosclerosis. Our data demonstrates VCAM-1 protein expression localized predominantly to the adventitia and endothelium in Ang II infused rats. Capers and coworkers have demonstrated infiltration of monocytes/macrophages predominantly in aortic adventitia in rats made hypertensive by Ang II infusion.41 Monocyte infiltration also occurs in the arterial walls of spontaneously hypertensive rats42 43 but is abolished with treatment with ACE inhibitors.43 Because VCAM-1 plays a significant role in monocyte adhesion to endothelial cells,4 5 the data from the present study and others suggest that the proatherogenic properties of the renin-angiotensin system may be mediated, in part, through Ang II-mediated induction of vascular inflammatory gene expression.
In summary, our findings demonstrate that Ang II, a potent
vasoconstrictor, growth factor, and activator of vascular
oxidant signals, stimulates NF-B activation and VCAM-l gene
expression in the vasculature. Ang II induced VCAM-1 expression serves
as a useful model for a novel, growth factor-mediated mechanism in
upregulating NF-B-driven vascular inflammatory genes. As such, this
model begins to link hypertension, a principal risk factor for
developing cardiovascular ischemic events, with
the inflammatory mechanisms involved in the pathogenesis of
atherosclerosis.
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Acknowledgments |
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This study was supported by the National Institutes of Health research grant PO1-HL-48667 (to R.W.A. and R.M.M.), R29-HL-60135 (to X.C. and R.M.M.), and by an unrestricted research grant from AtheroGenics, Inc. (to R.M.M.). This work was performed while Dr Medford was an Established Investigator of the American Heart Association.
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Footnotes |
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1 Drs Tummala and Chen contributed equally to this work.
Received March 12, 1999; revision received April 28, 1999; accepted May 5, 1999.
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