(Circulation. 2000;101:2889.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Antisense to LOX-1 Inhibits Oxidized LDL–Mediated Upregulation of Monocyte Chemoattractant Protein-1 and Monocyte Adhesion to Human Coronary Artery Endothelial Cells
From the Departments of Medicine and Physiology, University of Florida and VA Medical Center, Gainesville, Fla.
Correspondence to J.L. Mehta, MD, PhD, Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd, PO Box 100277 JHMHC, Gainesville, FL 32610. E-mail mehta{at}medmac.ufl.edu
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Abstract |
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Background—We have recently demonstrated a lectin-like receptor for oxidized (ox)-LDL (LOX-1) in human coronary artery endothelial cells (HCAECs). This receptor is upregulated by ox-LDL. The present study examined the significance of LOX-1 in monocyte adhesion to HCAECs and endothelial injury in response to ox-LDL.
Methods and Results—HCAECs were incubated in the presence of antisense oligodeoxynucleotides to the 5'-coding sequence of the human LOX-1 gene (0.5 µm/L). Basal LOX-1 mRNA and protein were suppressed by antisense LOX-1. Ox-LDL–mediated upregulation of LOX-1 was also suppressed by antisense LOX-1. Incubation of HCAECs with ox-LDL (40 µg/mL) for 24 hours markedly increased monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression as well as monocyte adhesion to HCAECs (P<0.01). After 48 hours of preincubation of HCAECs with antisense LOX-1, ox-LDL–mediated upregulation of MCP-1 and monocyte adhesion to HCAECs both were suppressed (P<0.01), whereas sense LOX-1 had no effect. Whereas antisense or sense LOX-1 alone (both 0.5 nmol/L) did not injure the cells, antisense LOX-1, but not sense LOX-1, reduced ox-LDL–mediated HCAEC injury, determined as LDH release (P<0.01). Activation of mitogen-activated protein kinase (MAPK) may play a critical role in signal transduction in ox-LDL–mediated alteration in MCP-1 expression, since antisense LOX-1, but not the sense LOX-1, completely inhibited the ox-LDL–induced MAPK activation.
Conclusions—These observations with the first use of a specific antisense to human LOX-1 mRNA suggest that LOX-1 is a key factor in ox-LDL–mediated monocyte adhesion to HCAECs.
Key Words: endothelium • receptors • lipoproteins • cell adhesion molecules • gene therapy
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Introduction |
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Monocyte infiltration into the vessel wall is a key initial step in the formation of the atherosclerotic lesion.1 2 After monocytes have adhered to the endothelium, they migrate into the intima, imbibe lipids, and become foam cells. The mechanisms by which monocyte adhesion to endothelium occurs involve the expression of monocyte chemoattractant protein-1 (MCP-1)3 and adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1.4
MCP-1 is chemotactic for monocytes both in vitro and in vivo.5 6 MCP-1 expression is upregulated in atherosclerotic lesions in both humans and experimental animals, suggesting that it may play a significant role in the pathogenesis of atherosclerosis. Studies have shown that cytokines7 and angiotensin II (Ang II)8 induce MCP-1 gene expression in vascular smooth muscle cells. Mitogen-activated protein kinase (MAPK) encoded by the extracellular signal–regulated kinase gene is a part of the family of serine/threonine protein kinases and is activated early in response to a variety of stimuli involved in cellular growth, transcription, and differentiation.9 The activation of MAPK plays an important signal transduction role in Ang II–induced MCP-1 gene expression.8 Modulation of monocyte adhesion to endothelial cells could be an important target in the therapy of atherosclerosis.
Oxidized low-density lipoprotein (ox-LDL) has been well known to play a
key role in the pathogenesis of atherosclerosis. Ox-LDL
causes endothelial injury, including activation,
dysfunction, necrosis, and apoptosis. We have recently
identified a lectin-like receptor for ox-LDL (LOX-1) in cultured human
coronary artery endothelial cells (HCAECs) and
showed that LOX-1 is upregulated by ox-LDL.10 Other
studies have shown that expression of LOX-1 is stimulated by tumor
necrosis factor-
and phorbol ester.11 Recent studies
from our laboratory12 show that Ang II also upregulates
LOX-1 expression and increases ox-LDL uptake by HCAECs. Another recent
study13 shows that LOX-1 expression is upregulated in
hypertensive rats.
The present study was designed to determine the significance of LOX-1 expression in monocyte adhesion to HCAECs as well as cell injury. We also examined the role of MCP-1 and MAPK in this process. These studies describe the development and use of a specific antisense to LOX-1 mRNA.
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Methods |
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Preparation of Antisense LOX-1 mRNA
Antisense phosphorothioate oligonucleotides (ODNs) and sense phosphorothioate ODNs (as controls) directed to 5'-coding sequence of the human LOX-1 mRNA14 were designed and manufactured by Biognostik GmbH. The antisense was synthesized as 16-mer (8 bases) targeted at the 5'-CAG TTA AAT GAG GCC G-3' part of the LOX-1 sequence. The corresponding control (sense) was 16-mer (8 bases) targeted at 5'-ACC TAC GTG ACT ACG T-3'. Hereafter, the antisense and sense to LOX-1 mRNA will be referred to as antisense LOX-1 and sense LOX-1, respectively.
In the present study, logarithmically growing endothelial cells were transfected by directly adding phosphorothioate ODNs into culture medium. Antisense ODNs are actively taken up by endothelial cells, partially through fluid-phase endocytosis and possibly also through the putative receptor protein p80 that facilitates the cellular uptake of negatively charged molecules like ODNs or heparin.15 Fluorescein (FITC)-labeled phosphorothioate ODNs were used to monitor cellular uptake and distribution. Labeled antisense ODNs met the same standards of purity and stability as antisense products. Whereas the cellular uptake of antisense ODNs may be enhanced through various cationic lipids, most of the cationic lipids are cytotoxic, and the treatment must be limited to 6 to 8 hours. In contrast, the half-life of antisense ODNs in serum containing culture media is >48 hours. Therefore, adding the antisense ODNs to the culture medium for the full duration of the experiment is more effective for experiments with a longer time frame.15 Details of the transfection process are provided below.
Cell Culture
The methodology for culture of HCAECs has been described earlier
by us.10 12 Fifth-generation HCAECs were used to examine
transfection of cells with antisense LOX-1 and to determine MCP-1
expression and monocyte adhesion. HCAECs were incubated with 3
different concentrations of antisense LOX-1 or sense LOX-1 (0.5, 2.0
and 4.0 µmol/L) for 12, 24, 48, and 72 hours to determine the
rate of transfection. Preliminary experiments showed that the uptake of
antisense LOX-1 was maximal with 0.5 µmol/L and after incubation
for 48 hours. At this time point, LOX-1 mRNA and protein was maximally
suppressed (see Results). Therefore, to study modulation of
ox-LDL–mediated effects, HCAECs were preincubated with antisense LOX-1
or sense LOX-1 (0.5 µmol/L) for 48 hours, and the cells were
then incubated with ox-LDL (40 µg/mL) for 24 hours to determine the
expression of LOX-1 and MCP-1 mRNA and protein. HCAECs incubated with
antisense LOX-1 or sense LOX-1 and ox-LDL were also used to examine
monocyte adhesion.
Preparation of Lipoproteins
Native LDL and ox-LDL were prepared as described
earlier.10 12 The TBARS content of ox-LDL was 18.2±0.28
versus 0.56±0.16 nmol/100 µg protein in the native LDL preparation
(P<0.01). Ox-LDL was extensively dialyzed against
Tris-saline. Ox-LDL was kept in 50 mmol/L Tris-HCl, 0.15 mol/L
NaCl and 2 mmol/L EDTA at pH 7.4 and was used within 10 days of
preparation.
Fluorescence Microscopy
To examine the uptake of antisense LOX-1, HCAECs were cultivated
on chamber slides in the presence of 0.5, 2.0, and 4.0 µmol/L
antisense LOX-1 or sense LOX-1 (each 0.5, 2.0, and 4.0 µmol/L)
for 12, 24, 48, and 72 hours, washed 3 times with PBS, overlaid with
PBS-glycerol (1:9) containing 2.5% DABCO (Janssen) and a coverslip,
and analyzed by fluorescence microscopy with an Olympus
BH2 microscope in the green (FITC) channel.
Reverse Transcription–Polymerase Chain Reaction for LOX-1
mRNA Expression
The method for LOX-1 mRNA expression was the same as described
earlier by us.10 12 In brief, 1.5 µL of the
reverse-transcript material of each sample of total RNA was amplified
with Taq DNA polymerase (Promega) with a primer pair specific to human
endothelial receptor (forward primer,
5'-TTACTCTCCATGGTGGTGCC-3', reverse primer,
5'-AGCTTCTTCTGCTTGTTGCC-3'). Polymerase chain reaction (PCR)
product was 193 base pairs. For PCR, 35 cycles were used at 94°C
for 40 seconds, 55°C for 1 minute, and 72°C for 1
minute.14 The reverse transcription (RT)-PCR–amplified
samples were visualized on 1.5% agarose gels by the use of ethidium
bromide. Human ß-actin was amplified as a reference for
quantification of LOX-1 mRNA. Relative intensity of bands of interest
was analyzed by NSF-300G scanner (Microtek) and scan
analysis software (Biosoft) and expressed as the ratio to
ß-actin mRNA band.
Western Analysis for LOX-1 Protein in HCAECs
The method for LOX-1 protein expression was same as described
earlier by us.10 12 The primary antibody to LOX-1 was a
gift of Dr T. Sawamura, Osaka, Japan. The second antibody was
purchased from Amersham Life Science.
RT-PCR for MCP-1 mRNA Expression
Total RNA (1 µg) extracted from cultured HCAECs was
reverse-transcripted with Oligo dT (Promega) and M-MLV reverse
transcriptase (Promega) at 37°C for 1 hour; 1.5 µL of the
reverse-transcripted material was amplified with Taq DNA polymerase
(Promega) with the use of a primer pair specific to human MCP-1
(forward primer, 5'-CAA ACT GAA GCT CGC ACT CTC GCC-3', reverse primer,
5'-ATT CTT GGG TTG TGG AGT GAG TGT TCA-3'). PCR product was 354 bp.
For PCR, 40 cycles were used at 95°C for 40 seconds, 62°C for 1
minute and 72°C for 1 minute.16 Human ß-actin was
amplified as a reference for quantitation of LOX-1 mRNA.
Western Analysis for MCP-1 in HCAECs
HCAEC lysates from each experiment (30 µg per lane) were
separated by 10% SDS-PAGE, transferred to nitrocellulose membranes.
After incubation in blocking solution (4% nonfat milk, Sigma),
membranes were incubated with 1:1000 dilution primary antibody
(monoclonal antibody to MCP-1, Santa Cruz Co) overnight at 4°C.
Membranes were washed and then incubated with 1:2000 dilution second
antibody (Amersham) for 1 hour, and the membranes were detected with
the enhanced chemiluminescence system, and relative intensities of
protein bands were analyzed by MSF-300G
Scanner.10 12
Isolation and Adhesion of Human Monocytes
Human peripheral monocytes were isolated as follows:
5 mL of heparinized fresh blood from fasting normolipemic subjects was
carefully layered onto a discontinuous gradient (2.5 mL of the 1.065
onto 2.5 mL of the 1.070) of Mono-Poly Resolving Medium (ICN
Pharmaceuticals). The monocyte band was collected by aspiration after
blood was centrifuged at 300g for 30 minutes in a
swinging bucket rotor at room temperature. Monocytes were washed twice
with balanced salt solution and the cells were resuspended in the
culture medium. Cells isolated by this method consisted of 94% to 98%
monocytes and showed intact function.17
Monocytes resuspended in the culture medium were added to the HCAECs
treated with antisense LOX-1 or sense LOX-1 and ox-LDL and incubated
under rotary conditions (60 rpm) at 37°C for 1 hour. This method was
based on the demonstration of optimal monocyte binding to
endothelial cells.17 18 After incubation,
the HCAECs were washed 3 times with HBSS, and the wash was discarded.
The HCAECs were examined under a phase-contrast microscope for adherent
monocytes. Adherent cells were counted in 
10 different fields
(magnification x100) in 6 separate flasks in each group of HCAECs. The
person counting the adherent monocytes was unaware of the
treatment.19
MAPK Immunoblotting
HCAEC lysates from each experiment were separated by 10%
SDS-PAGE and transferred to nitrocellulose membranes. After incubation
in blocking solution (4% nonfat milk), the membranes were incubated
overnight at 4°C with 1:1000 dilution rabbit polyclonal
phospho-specific MAPK antibodies (Calbiochem Co) that detect
p42 MAPK and p44 MAPK only
when catalytically activated by phosphorylation
at Tyr-204. Membranes were washed and then incubated with 1:2000
dilution second antibody (Amersham) for 1 hour, and the membranes were
detected with the enhanced chemiluminescence system. Thereafter, the
protein on the membrane was stripped and reprobed with MAPK antibody
(Calbiochem Co), and relative intensities of protein bands were
analyzed by MSF-300G Scanner.10 12
Measurement of LDH Release
One milliliter of sample was collected for determination of LDH.
A spectrophotometric enzyme activity method based on the oxidation of
lactate was used (Sigma). LDH activity was expressed as units per
milligram of protein.12
Data Analysis
All data represent the mean of duplicate samples from at
3 independently performed experiments. Data are presented as
mean±SD. Statistical significance was determined in multiple
comparisons among independent groups of data in which ANOVA and the
F test indicated the presence of significant differences. A
value of P
0.05 was considered significant.
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Results |
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Rate of Uptake of Antisense LOX-1 by HCAECs
The rate of uptake of antisense LOX-1 by HCAECs was measured by fluorescent-labeled phosphorothioate ODNs in 3 independent experiments. The peak uptake of antisense was observed at 48 hours after incubation with HCAECs. Incubation of HCAECs with antisense LOX-1 for 72 hours showed degradation of antisense LOX-1, but the intracellular content of antisense LOX-1 was still at high levels (Figure 1
, A and C).
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We compared 3 different concentrations (0.5, 2.0, and 4.0
µmol/L) of antisense LOX-1 and found that the higher concentrations
of antisense LOX-1 decreased the rate of uptake of antisense LOX-1 by
HCAECs, possibly related to the cytotoxic effect of high concentration
of antisense (Figure 1
, B and D). To reduce the nonspecific
effects of antisense LOX-1 on HCAECs, we chose 0.5 µmol/L of
antisense LOX-1 in subsequent experiments. The cells were preincubated
in the presence of 0.5 µmol/L antisense LOX-1 for 48 hours, and
the incubation then was carried out with ox-LDL (40 µg/mL).
Inhibition of LOX-1 Expression by Antisense LOX-1 mRNA
After incubation of HCAECs with antisense LOX-1 for 48 hours,
basal expression of LOX-1 mRNA as well as protein was significantly
reduced, as determined by RT-PCR and Western analysis (Figure 2). Incubation of HCAECs with ox-LDL
increased LOX-1 mRNA and protein expression (P<0.01 versus
baseline, n=6). However, preincubation of HCAECs with antisense LOX-1
completely inhibited ox-LDL–mediated upregulation of LOX-1 (Figure 3); in contrast, incubation with sense
LOX-1 did not affect basal or ox-LDL–stimulated LOX-1 expression
(Figures 2 and 3).
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Inhibition of MCP-1 Expression by Antisense LOX-1
Incubation of HCAECs with ox-LDL increased MCP-1 mRNA and protein
expression (P<0.01 versus control, n=6). Preincubation of
HCAECs with antisense LOX-1 markedly reduced ox-LDL–mediated
upregulation of MCP-1 mRNA and protein (P<0.01 versus
ox-LDL). In contrast, the presence of sense LOX-1 had no effect (Figure 4).
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Blockade of Monocyte Adhesion to HCAECs by Antisense LOX-1
Incubation of HCAECs with ox-LDL markedly increased the number of
adherent monocytes (P<0.01 versus control, n=6).
Ox-LDL–mediated monocyte adhesion to HCAECs was completely blocked by
preincubation of HCAECs with antisense LOX-1 but not by sense LOX-1
(Figure 5).
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Inhibition of ox-LDL–Induced Activation of MAPK by Antisense
LOX-1
The presence of ox-LDL in culture medium induced
phosphorylation of MAPK in HCAECs (P<0.01
versus control, n=6). Ox-LDL–mediated phosphorylation
of MAPK was completely inhibited by preincubation of HCAECs with
antisense LOX-1 but not by sense LOX-1 (Figure 6).
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Effect of LOX-1 on HCAEC Injury
Incubation of HCAECs with antisense LOX-1 or sense LOX-1 alone
(0.5 µmol/L) did not increase LDH release (n=6). On the other
hand, incubation of HCAECs with ox-LDL markedly increased LDH release
(P<0.01 versus control, n=6), indicating cell injury. This
effect of ox-LDL was completely blocked by preincubation of HCAECs with
antisense LOX-1 but not sense LOX-1 (Figure 7).
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Discussion |
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We recently identified LOX-1, a lectin-like endothelial receptor for ox-LDL, in HCAECs.10 12 The presence of abundant high-affinity LOX-1 on HCAECs10 provides a structural basis for incorporation of ox-LDL into these cells and resultant cellular activation, dysfunction, and injury.
In this study, we demonstrate for the first time the importance of LOX-1 with the use of a specific antisense to LOX-1 mRNA. We show that this antisense inhibits the expression of LOX-1. The biological effects of this antisense preparation probably result from both sequence-specific and hybridization-independent mechanisms.20 21 The antisense LOX-1 used in this study was constructed and controlled accordingly to recently published guidelines for the generation of reliable antisense ODNs.20 Minimizing the number of phosphorothioate modifications avoided nonspecific inhibition of DNA polymerases and RNAse H.22 Efficacy of low antisense concentrations ensured that the overall DNA synthesis was not reduced in a nonspecific manner.23 24 Further, we observed that the low concentration of phosphorothioate antisense LOX-1 (0.5 µmol/L) did not cause injury (LDH release) to HCAECs.
Specificity of the antisense LOX-1 in the present study was further confirmed by the following criteria: (a) this antisense inhibited basal and ox-LDL–stimulated LOX-1 mRNA and protein expression; (b) this antisense suppressed ox-LDL–induced upregulation of MCP-1 mRNA and protein as well as the activation of MAPK; (c) this antisense blocked ox-LDL–mediated monocyte adhesion to HCAECs; and (d) this antisense inhibited ox-LDL–mediated endothelial injury (LDH release). In contrast, sense (control) directed at the same LOX-1 mRNA sequence did not influence the effects of ox-LDL.
The monocyte is a critical cell in atherogenesis.1 2 Its adhesion to the endothelium is a key initial step in atherosclerosis. Increasing evidence has shown that specific adhesion molecules may be involved in monocyte adhesion to endothelial cells.4 These adhesion molecules include E-selectin, ICAM-1, VCAM-1, and MCP-1 on endothelial cells and members of the ß2-integrin (CD11a, CD11b, CD11c/18), the ß1 integrin (VLA-4) family, and MCP-1 on monocytes. Recent studies show that MCP-1 plays a crucial role in monocyte adhesion to endothelial cells.3 A study by Takahashi et al25 showed that recombinant human MCP-1 significantly increases monocyte adhesion. On the other hand, other studies26 27 showed that anti–MCP-1 antibody markedly decreases monocyte adhesion to endothelial cells. Experimental studies demonstrate that ox-LDL induces a 2- to 3-fold increase in MCP-1 mRNA and protein expression in monocytes28 and macrophages.29 Another study demonstrates that ox-LDL also increases MCP-1 mRNA and protein expression in endothelial cells.30 Chen et al8 showed that Ang II induces MCP-1 gene expression in rat vascular smooth muscle cells through a MAPK-dependent signaling mechanism. The present study demonstrates that ox-LDL induces a 2.5-fold increase in MCP-1 mRNA and protein expression in HCAECs. Importantly, we found that antisense directed at LOX-1 mRNA completely blocked the ox-LDL–mediated upregulation of MCP-1 gene and protein expression in HCAECs. This observation suggests that ox-LDL increases MCP-1 gene expression through a LOX-1–dependent signaling mechanism.
Increased MCP-1 expression in endothelial cells initiates monocyte recruitment on the endothelium and their transendothelial migration.31 32 Studies in nonhuman primate33 and other animal34 models have demonstrated that monocyte attachment to endothelial cells, their migration, and subendothelial localization are early events in the pathogenesis of atherosclerosis. Martin et al17 showed that incubation of endothelial cells with LDL significantly increases monocyte adhesion to endothelial cells as well as expression of soluble ICAM-1. In the present study, we demonstrated that incubation of HCAECs with ox-LDL increased monocyte adhesion to HCAECs 3-fold. In this process, expression of MCP-1 mRNA and protein expression was markedly upregulated. Antisense LOX-1 completely blocked ox-LDL–mediated monocyte adhesion to HCAECs, whereas sense LOX-1 had no effect. It is possible that other adhesion molecules (such as P-selectin and ICAM-1) also participate in ox-LDL–induced monocyte adhesion to HCAECs.
Experimental studies have shown that ox-LDL causes injury to the endothelial cells by activation of different signal transduction pathway, such as protein kinase C (PKC)35 and MAPK.36 The MAPK cascade is a signal transduction pathway that mediates many changes in cell function. Kusuhara et al36 found that ox-LDL stimulates MAPK activation in a time- and concentration-dependent fashion in rat smooth muscle cells. Stimulation of MAPK appears to involve PKC, since phorbol ester pretreatment for 24 hours can block MAPK activation. In the present study, we found that incubation of HCAECs with ox-LDL activated MAPK in HCAECs through action of LOX-1. The definitive evidence for this hypothesis came from the experiments wherein antisense to LOX-1 mRNA but not the sense control completely blocked ox-LDL–mediated MAPK activation. These findings suggest an important role for MAPK in signal conduction pathways by which ox-LDL contributes to altered cellular function associated with atherogenesis.
Increasing evidence37 has shown that ox-LDL mediates characteristic endothelial dysfunction, such as inhibition of cNOS activity. Ox-LDL appears to activate endothelial cells and induce vessel wall dysfunction in a time- and concentration-dependent manner. Studies by us35 and others38 demonstrate that ox-LDL induces apoptosis and cell injury. In the present study, we confirm that ox-LDL induces injury to HCAECs measured as LDH release. Importantly, we found that antisense to LOX-1 completely blocks ox-LDL–mediated injury to HCAECs. These findings provide clear evidence that LOX-1 plays a crucial role in ox-LDL–mediated endothelial dysfunction and atherosclerotic lesions.
In summary, this study with the use of a specific antisense directed at LOX-1 mRNA documents the pathophysiological significance of LOX-1 expression on HCAECs. The findings reported herein conclusively show that ox-LDL–induced monocyte adhesion to HCAECs is associated with upregulation of LOX-1 and increased MCP-1 gene expression. MAPK activation may be an important signal transduction pathway in the action of ox-LDL. These observations underscore the importance of LOX-1 in ox-LDL–mediated adhesion of monocytes to HCAECs as well as injury to HCAECs.
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Acknowledgments |
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These studies were supported in part by a Merit Review Award from the VA Central Office and a grant from the Department of Defense, Washington, DC.
Received October 7, 1999; revision received January 14, 2000; accepted February 1, 2000.
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