© 1997 American Heart Association, Inc.
Articles |
Effect of Advanced Glycation End Product–Modified Albumin on Tissue Factor Expression by Monocytes
Role of Oxidant Stress and Protein Tyrosine Kinase Activation
From INSERM U294 and Service d'Hématologie et d'Immunologie biologiques, CHU Xavier Bichat, Paris, France.
Correspondence to D. de Prost, Service d'Hématologie et d'Immunologie and INSERM (U294), CHU Bichat-Claude Bernard, 46 rue Henri Huchard, 75018, Paris, France.
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Abstract |
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Abstract Diabetes is associated with a hypercoagulable state that contributes to macrovascular complications, including cardiovascular events. The glycation reaction, a consequence of chronic hyperglycemia, has also been implicated in the pathogenesis of diabetic complications. Glycated proteins have receptors on monocytes and generate reactive oxygen species that can regulate the expression of a number of genes. As abnormal monocyte expression of tissue factor (TF), the main initiator of the coagulation cascade, is responsible for thrombosis in a number of clinical settings, we studied the effect of glycated albumin on monocyte TF expression. Mononuclear cells were incubated with glycated albumin for 24 hours, and monocyte TF activity was measured with a plasma recalcification time assay; TF antigen was measured by ELISA and TF mRNA by RT-PCR. Glycated albumin induced blood monocyte expression of the procoagulant protein TF at the mRNA level. Oxidative stress appeared to be involved in this effect, as the antioxidant N-acetylcysteine diminished TF mRNA accumulation in stimulated monocytes. Hydroxyl radicals, which may be generated inside cells from H2O2 via the Fenton reaction, also appeared to be involved in this effect, as hydroxyl radical scavengers downregulated TF activity and antigen levels (but not TF mRNA). Finally, the involvement of activated protein tyrosine kinase in the transmission of the signal from the membrane to the nucleus was suggested by the inhibitory effect of herbimycin A. These results point to a new mechanism for the hypercoagulability often described in diabetic patients and suggest that antioxidants or protein tyrosine kinase inhibitors might be of therapeutic value in this setting.
Key Words: glycation • oxidant stress • tissue factor • monocyte • thrombosis
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Introduction |
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Advanced glycation end products are nonenzymatically glycated adducts that form on proteins with long half-lives and accumulate at an accelerated rate in diabetes. A receptor system for AGEs has been described on monocyte/macrophages; it includes a 60-kD and a 90-kD protein identified in rat liver homogenates,1 the macrophage scavenger receptor,2 and a 35-kD protein named RAGE, which belongs to the immunoglobulin superfamily. RAGE is also expressed by endothelial cells and smooth muscle cells, as well as by certain neurons and mesangial cells.3
In monocytes, the interaction of AGE-modified proteins with AGE
receptors triggers the synthesis and release of cytokines,
particularly interleukin-1ß and TNF-
.4 AGEs also
induce human monocytes to produce insulin-like growth factor and
platelet-derived growth factor.5 6 The interaction of
AGEs with RAGE has also been shown to result in oxidant stress, based
on the generation of thiobarbituric acid-reactive substances, induction
of heme oxygenase type I and activation of
NF-
B.7 The signal pathways responsible for gene
expression are not completely understood. AGEs themselves have been
shown to generate reactive oxygen intermediates (mainly superoxide
anion and hydrogen peroxide [H2O2]) in vitro
and in vivo.8 Once generated in proximity to the cell
membrane, H2O2 can penetrate rapidly within the
cell, whereas other activated oxygen species cannot. Inside the
cell, H2O2 can react with iron or copper in the
Fenton reaction; the resulting hydroxyl radical may be an important
mediator of the H2O2 action on cells.
TF, a transmembrane glycoprotein, is the receptor for plasma factors VII and VIIa. The TF-VIIa complex is now considered as the main initiator of the coagulation cascade. TF is not normally expressed by circulating monocytes, but it can be synthesized in response to a number of inflammatory molecules. Abnormal TF expression by monocytes is responsible for the thrombosis occurring in sepsis, inflammatory diseases, and acute coronary syndromes.9 Excessive activation of coagulation has often been observed in diabetic patients10 and may play a role in the onset of vascular complications.
The first aim of this study was to assess whether AGEs induce monocytes to produce and express TF. The second aim was to determine whether reactive oxygen intermediates, especially hydroxyl radicals, are involved in this effect. The role of PTK activation was also evaluated by using herbimycin A, an inhibitor of these enzymes.
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Methods |
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Preparation of AGE-Alb
AGE-Alb was prepared by incubating human serum albumin (Biotransfusion) in PBS (150 mmol/L, pH 7.4) with 250 mmol/L D-glucose at 37°C for 6 weeks in the presence of 1.5 mmol/L PMSF, 0.5 mol/L EDTA, 2 µg/mL aprotinin (Trasylol, Bayer), 0.5 µg/mL leupeptin, and antibiotics (100 µg/mL penicillin and 143 µg/mL streptomycin). Control albumin was incubated in the same conditions without glucose. At the end of the incubation period, both solutions were extensively dialyzed against PBS. The endotoxin content was measured in a chromogenic assay (Coatest Endotoxin, Chromogenix) and was less than 0.05 ng/mL. Glucose content was less than 3.5 mmol/L. AGE-specific fluorescence was determined at 460 nm after excitation at 390 nm by using an AMINCO SPF 500 ratio spectrofluorometer as described by Kirstein et al.5 AGE-Alb contained 25 AGE units per 10 mg of protein, while native albumin contained 0.6 AGE units per 10 mg of protein.
Cell Preparation
Peripheral blood cells were obtained from healthy
donors by venipuncture, using EDTA as anticoagulant.
Mononuclear cells isolated by the Ficoll-Hypaque gradient technique
contained 20% to 30% monocytes, 60% to 70% lymphocytes, and fewer
than 10 platelets per monocyte.11 Mononuclear cell
suspensions (1x106 monocytes per milliliter) were
incubated with a fivefold dilution of AGE-Alb or control
albumin, for 24 hours in RPMI-1640 supplemented with
penicillin, streptomycin, pyruvate, L-glutamine, and
nonessential amino acids (BioWhittaker). The polypropylene tubes
(Polylabo) used for incubating the cells did not allow monocytes to
adhere. As monocytes are extremely sensitive to traces of contaminating
endotoxin, polymyxin B (2 µg/mL) was added to the culture
medium in all experiments. It was verified that this concentration of
polymyxin B did not alter basal TF activity. The stimulating effect of
phorbol myristate acetate was not modified either. At the end
of the incubation, the medium was discarded and cells were washed and
stored for less than 1 week at -80°C until TF assay or RNA
extraction. Cell viability was respected in all the experimental
conditions, as measured by lactate dehydrogenase release or trypan blue
exclusion.
TF Assays
Cells were lysed and TF activity was quantified in a one-step
plasma recalcification time assay.12 To confirm that
procoagulant activity was TF, residual procoagulant activity was
measured in some experiments, after incubating the cell lysate for 10
minutes with a pool of neutralizing anti-TF monoclonal antibodies
(TF8-5G9, TF8-6B4, and TF9-9C3) generously provided by T.S. Edgington
(the Scripps Research Institute, La Jolla, Calif). Neutralizing
antibodies were used at a concentration of 10 µg/mL. TF
antigen was determined by an ELISA method (Imubind TF kit, American
Diagnostica Inc) according to manufacturer's instructions,
with minor modifications.11
RT-PCR Analysis
RNA was extracted from mononuclear cells with the RNA PLUS
reagent (Bioprobe Systems). Five micrograms of total RNA was incubated
for 5 minutes at 65°C with 3 µmol/L of random hexamers
(Perkin-Elmer). After 10 minutes at room temperature, reverse
transcription was carried out for 1 hour at 37°C in a 50-µL
reaction volume containing 50 U of murine leukemia virus reverse
transcriptase (Perkin-Elmer), 40 U of RNAse inhibitor
(Perkin-Elmer), and all four deoxyribonucleoside triphosphates (dNTPs,
1 mmol/L each) in reaction buffer (50 mmol/L
KCl, 10 mmol/L Tris HCl, pH 8.3, 5 mmol/L
MgCl2). PCR reactions were run in a Trio-Thermoblock
apparatus (Biometra) with 2 µL of the retrotranscription
reaction product in a total volume of 100 µL with 0.2
mmol/L each dNTP, 0.4 µmol/L each primer, and 1 U
of Taq DNA polymerase (ATGC). The reaction cycles were
94°C for 1.5 minutes, 62°C for 3 minutes, and 72°C for 3 minutes
(30 cycles). Sense and antisense primers for TF were those described by
Bartha et al.13 Semiquantitative competitive RT-PCR was
used to correct for variations in amplification efficiency in each
reaction and to calculate relative changes in mRNA levels. This was
done using the PCR MIMIC construction kit (Clontech Laboratories),
which enables a PCR mimic to be generated and used as a competitive
internal standard in PCR amplification. The PCR mimic consists of a
nonhomologous DNA fragment that bears the recognition sequences for TF
primers at each extremity. The PCR mimic and target template thus
compete for the same primers in the same reaction. Equal amounts of the
mimic were included in each PCR reaction. Amplification products
were subjected to electrophoresis in 2% agarose gels containing
ethidium bromide and were photographed with Polaroid 665 negative film.
RNA was quantitated by scanning the bands with a Macintosh One-Scanner
densitometer; the density of each band was normalized to the density of
the mimic band and plotted in arbitrary units.
Statistics
Results, expressed as mean±SEM, were compared using
nonparametric tests: the Kruskal-Wallis test was used for
analysis of variance, while the Mann-Whitney U test
and the Wilcoxon test were used for unpaired and paired
data, respectively.
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Results |
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Effect of AGE-Alb on TF Expression by Mononuclear Cells
To study the kinetics of the effect of AGE-Alb on monocyte TF production, the cells were incubated with AGE-Alb for 4, 12, 24, and 48 hours. As shown in Fig 1
, inset, TF activity peaked at 24 hours. Subsequent experiments were thus
performed at 24 hours. Incubation of mononuclear cell suspensions for
24 hours with AGE-Alb (1 vol in 4 vol of culture medium) was associated
with a 5.6-fold increase in procoagulant activity expressed by viable
cells (from 30 with control albumin to 170 mU/106
monocytes, n=2); in lysed cells, AGE-Alb induced a significant
(P<.05) 5.2-fold increase in procoagulant activity (from
395±90 with control albumin to 2076±336 mU/106
monocytes; Fig 1A). Procoagulant activity was identified as TF, as more
than 99% was abolished by a cocktail of neutralizing monoclonal
antibodies directed against TF (data not shown). Moreover, when cells
were treated with AGE-Alb, TF antigen levels increased from 147±70
pg/106 monocytes (control albumin) to
896±198 pg/106 monocytes (n=6, P<.05;
Fig 1A). A good correlation was found between TF activity and TF
antigen levels (r=.6, P<.05, y=0.4 x+113.8). The
addition of increasing concentrations of AGE-Alb (1:10 and 1:5) to the
incubation medium led to a concentration-dependent increase in TF
activity (590 and 2000 mU/106 monocytes, respectively, mean
of two experiments, versus 85 and 396 with control albumin at
the same concentrations). The effect of costimulating the cells with
200 U/mL recombinant TNF- (Genzyme) was then evaluated. The cells
were incubated for 20 hours with AGE-Alb or control albumin,
followed by a 4-hour incubation with or without TNF. The addition of
TNF had a direct effect on the induction of TF activity in control
cells (which increased from 200 to 950 mU/106 monocytes);
when TNF was added to AGE-Alb–treated cells the TF activity level
increased from 1050 to 2000 mU/106 monocytes, an increase
that corresponds to the sum of the activity induced by AGE-Alb and TNF
separately (n=2).
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, TF activity; 
, TF antigen; *P<.05
versus control albumin. B, After 24 hours of incubation with
albumin (Alb; lane 1), AGE-Alb (lane 2), or AGE-Alb+10 µg/mL
cycloheximide (lane 3), total RNA was extracted and used for RT-PCR
studies. A PCR mimic (340 bp) was used as competitive internal standard
in PCR amplification. The intensity of the TF band (235 bp) was
determined by densitometry, normalized to the density of the mimic
band, and plotted as arbitrary units. Results are the mean±SEM of
three experiments. One representative experiment is
shown. L indicates 100-bp DNA ladder.
To assess the level of action of AGE-Alb, TF mRNA was studied after
reverse transcription and amplification by PCR. After treatment with
AGE-Alb for 24 hours, TF transcripts were readily detected as the
expected band of 235 bp (1.1 arbitrary units), which remained faint
(0.2 arbitrary units) in cells incubated with unmodified
albumin (Fig 1B
). As the primers for the TF gene were separated
by one intron (intron 5), the observed band could only have originated
from spliced mRNA (not from genomic DNA). To determine whether AGE-Alb
induction of TF mRNA required de novo protein synthesis, monocytes were
stimulated in the presence of the translational inhibitor
cycloheximide. Cycloheximide (10 µg/mL) completely suppressed
AGE-Alb–induced TF mRNA accumulation, showing that the induction
mechanisms elicited by AGE-Alb required de novo protein synthesis.
Effect of the Antioxidant N-Acetylcysteine on TF
Expression
As the interaction of AGEs with RAGE has several effects in
monocytes through the enhancement of cellular oxidant stress, the role
of reactive oxygen species in AGE-induced TF production was
assessed using the antioxidant N-acetylcysteine.
N-Acetylcysteine acts mainly by increasing levels of the
endogenous antioxidant reduced glutathione, and
consequently increases H2O2
metabolism by the glutathione peroxidase system. Incubation
in the presence of N-acetylcysteine resulted in
concentration-dependent inhibition of TF activity (Fig 2A) and TF antigen expression (Fig 2B);
(>90% suppression at 30 mmol/L). Moreover, TF mRNA was
almost completely suppressed at this concentration (Fig 2C).
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Effect of Hydroxyl Radical Scavengers
The role of hydroxyl radicals, which can be generated
intracellularly via the interaction of H2O2
with iron or copper, was evaluated by using two hydroxyl radical
scavengers: TU and DMTU. Mononuclear cells were incubated with
increasing concentrations (0.5 to 25 mmol/L) of TU or DMTU.
These agents caused a concentration-dependent reduction in TF
procoagulant activity (Fig 3A and 3B). At
25 mmol/L, residual TF activity was 49±8% with TU,
16±3% with DMTU, and 114±12% with 25 mmol/L urea (used
as a molarity control). No direct effect of these compounds on the TF
assay occurred, as their addition to the culture medium at 24 hours did
not alter the TF activity expressed by the cells. The effect of these
inhibitors on TF protein expression was analyzed by
means of ELISA. The residual induction of TF antigen by AGE-Alb was
41±15% and 15±5.9%, at 25 mmol/L TU (n=5) or DMTU
(n=6), respectively, while residual TF activity was 55±9.9% and
20±8%, respectively, in paired experiments. We concluded that TF
antigen expression fell in parallel with TF activity. By contrast (Fig 3C), TF mRNA expression induced by AGE-Alb was not inhibited when cells
were simultaneously treated with TU or DMTU.
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Effect of Herbimycin A, an Inhibitor of PTK
As H2O2 activates PTK in B cells,
we tested the effect of herbimycin A on AGE-Alb–induced TF expression.
As shown in Fig 4A, herbimycin inhibited
AGE-Alb TF activity in a concentration-dependent manner; moreover,
1 µmol/L herbimycin A completely suppressed
AGE-Alb–induced accumulation of TF antigen and TF mRNA (Fig 4B).
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Discussion |
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Diabetes is associated with a hypercoagulable state,10 14 which contributes to macrovascular complications, including cardiovascular events. The glycation reaction, a consequence of chronic hyperglycemia, has been implicated in the pathogenesis of diabetic complications. Schiff-base adducts and Amadori products produced through the glycation reaction generate reactive oxygen species (including superoxide anion and H2O28 ) that may regulate the expression of a number of genes.15 16 The results of this study show that glycated albumin induces blood monocyte expression of the procoagulant protein TF at the mRNA level. Oxidative stress may have a role in this effect, as the antioxidant N-acetylcysteine attenuated the accumulation of TF mRNA in AGE-Alb–stimulated monocytes. Hydroxyl radicals, which may be generated inside the cell from H2O2 via the Fenton reaction, also appear to be involved in this effect, as hydroxyl radical scavengers downregulated the expression of TF activity and antigen, but not that of TF mRNA. Finally, the involvement of activated PTK in the transmission of the signal from membrane to nucleus was suggested by the inhibitory effect of herbimycin A.
Incubation of the cells with AGE-Alb led to a time- and
concentration-dependent increase in TF activity, which was maximal at
24 hours and decreased thereafter. The TF expression of intact cells
was about 10% that of lysed cells. This distribution, which is similar
to that obtained with other well-studied agonists such as endotoxin, is
considered to reflect the potentiation of TF activity by lysis-induced
exposure of anionic phospholipids.17 This 5.2-fold
increase in TF activity was accompanied by a 6-fold increase in TF
antigen and a similar increase in TF mRNA. Endotoxin contamination had
no role in this effect, as all albumin preparations, reagents,
and media were discarded if more than 0.05 ng/mL was detected;
moreover, polymyxin B was added to all the culture media. Costimulation
of the cells with TNF- and AGE-Alb was associated with a response
corresponding to the sum of the activity induced separately by the two
agents. Esposito et al18 have reported a similar effect of
glycated albumin on binding to endothelial
cells; in these cells, TF activity was maximal after 60 hours of
incubation with glycated albumin. In these cells, however, TNF
and AGE-Alb had a synergistic effect. Interaction of AGEs with
mononuclear phagocytes induces an activated phenotype
manifested by induction of mRNA corresponding to several inflammatory
cytokines and growth factors, including interleukin 1ß,
TNF,4 19 and insulin-like growth factor.5 TF
mRNA accumulation induced by AGE-Alb was completely suppressed by
cycloheximide pretreatment of the cells, suggesting the involvement of
newly synthesized proteins in this effect. Interleukin 1ß and TNF are
known TF inducers and might at least partly mediate TF
production.20
The antioxidant N-acetylcysteine completely suppressed the
induction of TF activity, TF antigen, and TF mRNA expression after 24
hours of monocyte incubation with glycated albumin. This
observation strongly suggested that oxidant stress was responsible for
TF gene expression. N-Acetylcysteine, a sulfhydryl-group
donor, is easily transported into the cell, where it is deacylated and
increases the thiol pool (primarily reduced glutathione). Glutathione
peroxidase is the key peroxide detoxification system, and the
availability of reduced glutathione is essential for this
role.21 Previous studies have shown that glycated proteins
can generate reactive oxygen intermediates7 8 such as
superoxide anion, which is further reduced to
H2O2. Monocyte interactions with AGEs appear to
be mediated at least in part by RAGE and a lactoferrin-like
polypeptide. RAGE is an integral membrane protein that belongs to the
immunoglobulin superfamily.3 22 Lactoferrin-like
polypeptide binds noncovalently and with high affinity to the
extracellular domain of RAGE, and the resulting complex also binds
AGEs. Yan and coworkers7 showed that, on binding to RAGE,
AGE-Alb induces oxidant stress characterized by generation of
thiobarbituric acid reactive substances, activation of NF-B, and
induction of heme oxygenase mRNA. This effect was inhibited
by superoxide dismutase and catalase, strongly suggesting a central
role of H2O2 via NF-B activation. In keeping
with this sequence of events, a nonconsensus NF-B sequence is
present in the LPS response element of the TF promoter and is
involved in transcriptional activation of the gene in response to LPS
and cytokines.23
Since Schreck and Bauerle24 first postulated that certain
oxygen free radicals may play the role of intracellular messengers, the
regulation of the TF gene by oxidant stress has been reported in
several studies. In cultured endothelial cells, oxygen
free radicals induce TF messenger RNA transcription25 and
expression of TF procoagulant activity. Furthermore, isolated rabbit
hearts exposed to oxygen free radicals and hearts subjected in vivo to
ischemia and reperfusion, showed a marked increase in TF
activity that was abolished by oxygen radical scavengers such as
superoxide dismutase. The involvement of oxygen free radicals in LPS-
and cytokine-induced TF expression by
endothelial cells has also been suggested, as PDTC, a
specific inhibitor of the NF-B pathway, abrogated this
effect at the mRNA level.26 PDTC scavenges free radicals
and chelates transition metal ions. PDTC and
N-acetylcysteine inhibited LPS-induced TF activity in
monocytes/macrophages, but neither of these agents reduced
LPS-stimulated TF mRNA accumulation, thereby suggesting a
posttranscriptional mechanism (impaired translation, or degradation of
newly translated protein).27 These results also suggest
that different regulatory mechanisms might be at work in monocytes and
endothelial cells. Our results are in keeping with a
report that TNF production by mononuclear phagocytes in
response to glycated albumin is inhibited by
N-acetylcysteine.19 This latter study also
clearly showed that TNF production was dependent on AGE binding
to RAGE.
However, it is not clear which form of activated oxygen species
underlies the effect of AGEs on the signaling pathway that leads to
activation of NF-B and gene expression. The reactive oxygen
intermediates generated outside the cell, in close contact with
RAGE-bound AGEs, lead to the formation of H2O2,
which, unlike other activated oxygen species, readily crosses
cell membranes. Once inside the cell, H2O2 can
react with iron or copper in the Fenton reaction to form the hydroxyl
radical, which may be an important mediator of
H2O2 action. Our results with two hydroxyl
radical scavengers, TU and DMTU, suggest that induction of TF activity
and antigen expression by AGEs is dependent on hydroxyl radical
formation. At 25 mmol/L TU or DMTU, the residual TF
activity was 49% and 16%, respectively, relative to values obtained
without the inhibitors. TF activity and antigen levels fell
in parallel, suggesting that the observed effect was secondary to
decreased production of the protein. TU and DMTU did not,
however, alter TF mRNA expression, pointing to a posttranscriptional
mechanism. TU and DMTU are low-molecular-weight, membrane-permeable
hydroxyl scavengers. A suppressive effect of hydroxyl radical
scavengers has been reported28 on the expression of
interleukin-8 in response to LPS, PHA, and immune complexes; in this
case, however, mRNA levels fell in parallel to those of the released
cytokine.
Given the growing body of evidence that reactive oxygen species modulate PTK activities,29 we studied the effect of herbimycin A, an inhibitor of PTK, on AGE-Alb–induced TF expression. Herbimycin A clearly reduced both TF activity and TF mRNA accumulation in response to AGE-Alb. This is consistent with the fact that H2O2 induces tyrosine phosphorylation and inhibits protein tyrosine phosphatase activities in several cell types.29 All protein tyrosine phosphatases have a conserved cysteine residue in their catalytic domain, which must be in reduced form for full activity; these enzymes are thus strongly dependent on the intracellular redox state, which is controlled by glutathione. Taken together, our results suggest that the effect of glycated albumin on TF expression by monocytes might be the result of two associated mechanisms. H2O2 (or a metabolite) might act at the mRNA level (increasing mRNA transcription and/or stability) via the activation of PTK, as indirectly suggested by the effect of N-acetylcysteine and herbimycin A; hydroxyl radicals, by contrast, would act through a posttranscriptional mechanism, as their scavenging does not alter TF mRNA expression.
These results also point to a new mechanism for the hypercoagulability often described in patients with diabetes. The induction of TF expression on circulating blood monocytes by glycated proteins confers a procoagulant phenotype that might partly be responsible for the thrombotic complications in these patients. Indeed, recent observations strongly suggest that thrombosis is initiated via the TF pathway in vivo. TF antigen and active TF have been identified in human coronary atheroma30 and were shown to be associated with plaque thrombi, which play an important role in the pathogenesis of acute coronary syndromes. TF-producing monocytes and macrophages of the atherosclerotic plaque31 may represent therapeutic targets for the prevention of thrombotic complications. Furthermore, antioxidants or PTK inhibitors32 might be of therapeutic value in these patients.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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These studies were supported by the Fondation de France and by Hoechst Laboratories. Anti-TF monoclonal antibodies TF8-5G9, TF8-6B4, and TF9-9C3 were generously provided by T.S. Edgington of the Scripps Research Institute, La Jolla, Calif.
Received December 31, 1996; accepted April 15, 1997.
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