From the Laboratoire d'Hématologie (D.C., B.J.), Service de
Cardiologie et Hémodynamique (C.B., E.P.M.), Service des Soins
Intensifs (P.A.), Service Commun d'Imagerie Interventionnelle (T.L.T.,
I.S., T.M.), Centre Hospitalier Régional Universitaire and
Faculté de Médecine, Lille, France, and Section of
Cardiovascular Medicine (M.D.E.), Yale University, New Haven, Conn.
Correspondence to Brigitte Jude, MD, Laboratoire d'Hématologie, Hôpital Cardiologique, Boulevard du Professeur J Leclercq, 59037 Lille Cedex, France. E-mail b.jude{at}chru_lille.fr
Methods and Results—We studied TF expression in 18 rabbits with
atherosclerosis induced by bilateral iliac damage and
10 weeks of a 2% cholesterol diet. Six weeks after the
initiation of the diet, an angioplasty was performed. After
angioplasty, the surviving rabbits (n=15) were randomized to receive
L-arg (2.25%) supplementation in drinking water
(L-arg group, n=8) or no treatment (untreated group, n=7).
TF expression was evaluated in mononuclear cells from
arterial blood in the presence and absence of endotoxin
stimulation. Monocyte TF expression, as assessed with an amidolytic
assay, did not differ significantly before or after the induction of
atherosclerotic lesions (87±15 versus 70±12 mU of TF/1000 monocytes,
P=NS). Endotoxin-stimulated TF activity increased
significantly 4 weeks after angioplasty (138±22 versus 70±12 mU of
TF/1000 monocytes, P=0.02). This increase was blunted by
L-arg (43±16 mU of TF/1000 monocytes,
P=0.01).
Conclusions—This study demonstrates that angioplasty-induced
plaque rupture is associated with a marked increase in monocyte TF
response that is blunted by the oral administration of
L-arg. This suggests that the documented antithrombotic
properties of NO may be related in part to an inhibitory
effect on monocyte TF response.
The TF gene in monocytes is controlled by several transcription factors
activated by external signals, such as growth factors,
inflammatory cytokines (interleukin-1ß and tumor necrosis
factor-
Nitric oxide (NO) plays an important role in vascular regulation
through its vasodilatory,11
antiatherogenic,12 and antithrombotic properties.
NO inhibits platelet adhesion and
aggregation13 and modulates smooth muscle cell
proliferation and migration.14 NO limits
cytokine-induced endothelial
activation15 16 and modulates the expression of
monocyte chemoattractant protein-1 in cultured
endothelial cells17 through a
decrease in NF-
We hypothesized that contact between atherosclerotic plaques and blood
could increase TF expression by circulating monocytes and that NO might
limit this response. To test these hypotheses, we used a rabbit model
of induced atherosclerosis (bilateral iliac injury and
an atherogenic diet), and we performed angioplasty when atherosclerotic
lesions were established. In this model, we studied the effect of
L-arg, the endogenous NO precursor, on TF
expression by circulating monocytes.
Induction of Atherosclerosis
Angioplasty
Study Groups
Blood Samples
Blood samples collected in lithium heparin and in EDTA were diluted to
decrease measurement artifacts due to severely lipemic blood.
Isolation of Mononuclear Cells and Cell Culture
All reagents and culture supplies used in the study were free of
endotoxin (chromogenic limulus amebocyte lysate [LAL]
assay sensitivity, 0.025 endotoxin unit [EU]/mL). An aliquot of the
freshly isolated mononuclear cells, referred to as noncultured cells,
was frozen at -80°C. Other aliquots of cell preparations
(3x106 cells/mL) suspended in RPMI 1640 without
fetal calf serum were cultured for 16 hours at 37°C in a humidified
5% CO2 atmosphere, without or with stimulation
by endotoxin at 5000 EU/mL (Escherichia coli 055:B5; Sigma
Chemical); these are referred to as unstimulated and stimulated cells,
respectively. At the end of the incubation period, monocytes were
resuspended and frozen at -80°C.
TF Activity Assay
The amidolytic activity was characterized as TF according to a
neutralization procedure using mouse monoclonal antibody
anti-rabbit–TF (AP-1): diluted (1:18) antibody (25 µL) was incubated
with diluted TF standard or lysed cell suspensions for 30 minutes at
37°C. Then, the mixture was tested for amidolytic activity.
Immunocytochemical Staining
Cells were fixed in buffered
acetone/acetone/paraformaldehyde 4%. Mouse isotype
antibody was used as a negative control. Anti-TF labeling is seen as a
bright red color in the cytoplasm, with membrane reinforcement in the
most positive cells (Figure 3
Assays on Plasma Samples
Serum total cholesterol and triglyceride
(TG) levels were determined with enzymatic assays using
cholesterol esterase plus cholesterol oxidase
and glycerol-3-phosphate oxidase, respectively (Biomerieux). The
L-arg level was determined after deproteinization with 10%
sulfosalicylic acid and was analyzed for free arginine (LC 300;
Biotronic Instrument). Prothrombin time was measured by use of an
automated clotting assay with calcified thromboplastin (Biomerieux).
Fibrinogen levels were measured according to the Clauss technique
(Biomerieux).
Factors II, V, and VII+X levels were determined by an automated
clotting assay (STA; Stago) with the use of calcified rabbit brain
thromboplastin and human factor–deficient plasma (Stago).
Statistical Analysis
Total White Blood Cell, Monocyte, and Platelet Counts
There was no difference between the L-arg group and the
untreated group for any of these parameters.
Monocyte TF Activity
Early Effects of Hypercholesterolemia and
Iliac Denudation
In stimulated cells, a significant decrease in monocyte TF activity was
observed at 3 weeks (30±6 versus 87±15 mU of TF/1000 monocytes,
P<0.005), followed by a trend toward normalization after 6
weeks (70±12 mU of TF/1000 monocytes, P<0.005 versus 3
weeks) (Figure 4A
The results were similar when TF monocyte content was expressed per
milliliter of blood (Figure 4B
Effects of Angioplasty With and Without L-Arg
Supplementation
In stimulated cells, TF activity was significantly greater 4 weeks
after angioplasty in the untreated group compared with the value
observed just before angioplasty (138±22 versus 70±12 mU of TF/1000
monocytes, P=0.02). This increase in stimulated TF activity
was significantly less in the L-arg group than in the
untreated group (43±16 versus 138±22 mU of TF/1000 monocytes,
P=0.01) (Figure 5A
The results were similar when TF monocyte content was expressed per
milliliter of blood (Figure 5B
Immunocytochemistry
Changes in Other Parameters
There was no difference between the L-arg group and the
untreated group with respect to the levels of plasma coagulation
factors (Table 2
Effect of Endothelial Denudation and
Hypercholesterolemia
Additional significant changes in the levels of coagulation factors and
platelets were observed. A decrease in the platelet count and
the levels of fibrinogen occurred, suggesting an associated consumption
process. Vitamin K–dependent factors (factors VII and X) increased
significantly, as reported previously.27 28 This
increase has been shown to reflect an increase in the rate of
synthesis, or activation.
Effects of Angioplasty
Effect of L-Arg
NO can also inhibit the transcriptional protein NF-
Study Limitations
In summary, exogenous administration of L-arg, the NO
precursor, blunts the increase of TF response in stimulated monocytes
after angioplasty in a rabbit model of induced
atherosclerosis. These results suggest that the
antithrombotic properties of NO could also be related to an
inhibitory effect on monocyte TF response, in addition to
its known effects on endothelial and platelet
functions. Local generation of sufficiently high amounts of NO by
endothelial cells or macrophages, through oral
L-arg supplementation, may induce a reduction in
TF-mediated hemostatic activation in complicated
atherosclerosis. L-Arg is known to restore
endothelium-dependent dilation and to inhibit
platelet aggregation in humans.39 40 As a
therapeutic agent, L-arg may have a potential clinical
impact via these antithrombotic properties in the treatment or the
prevention of human vascular diseases, including
atherosclerosis, thrombosis, and septic shock. A
complete understanding of the physiological and
pathophysiological roles of L-arg must
await further studies.
Received February 11, 1998;
revision received June 3, 1998;
accepted June 5, 1998.
© 1998 American Heart Association, Inc.
Basic Science Reports
Enhanced Monocyte Tissue Factor Response After Experimental Balloon Angioplasty in Hypercholesterolemic Rabbit: Inhibition With Dietary L-Arginine
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—There is evidence
that tissue factor (TF) is a major contributor to the thrombogenicity
of a ruptured atherosclerotic plaque. Nitric oxide (NO) has
antiatherogenic and antithrombotic properties. We investigated whether
L-arginine (L-arg), the endogenous
precursor of NO, might affect the ability of monocytes to produce
TF.
Key Words: tissue factor • monocytes • nitric oxide • atherosclerosis
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Monocytes and macrophages are involved in the
progression of atherosclerosis and in the pathogenesis
of thrombosis.1 2 Monocytes can express tissue
factor (TF),3 4 which is present in
atheromatous plaques.5 6 There is
evidence that TF is a major contributor to the thrombogenicity of
ruptured plaques.7 
), oxidized LDLs, and endotoxin. The induction of the TF gene
in monocytes stimulated by endotoxin is mediated by the interaction of
transcription factors such as activator protein-1 (AP-1)
and nuclear factor-
B (NF-B) with their corresponding binding
sites that are present in the TF promoter
region.8 The TF gene shares these regulatory
mechanisms with other genes involved in leukocyte adhesion to
endothelial cells, activated through a common
oxidant-sensitive transcriptional pathway leading to the expression of
endothelial proteins (eg, vascular cell adhesion
molecule-1, intercellular adhesion molecule-1, and monocyte
chemoattractant protein-1).9 10 B–binding activity. L-Arg decreases the
adhesiveness of monocytes to the endothelium through
inhibition of endothelium/leukocyte adhesion molecule
transcription18; L-arg limits the
progression of
atherosclerosis,12 19 restores
endothelium-dependent
vasodilation,20 21 and limits intimal
proliferation of vascular smooth muscle cells after
angioplasty.21 22
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Male New Zealand White rabbits (Charles River, Saint Aubin
lès Elbrug, France) with an initial body weight of 3.0 to
3.5 kg were used for this study. All experiments were conducted in
compliance with the position of the American
Physiological Society on research animal
use.
Bilateral iliac atherosclerosis was induced
according to the method described by Kakuta et
al.23 Rabbits were anesthetized with
ethyl carbamate (1 g/kg IV): after exposure of the femoral arteries, a
3F Fogarty balloon catheter was inserted to a distance of 20 cm,
inflated until contact was made with the endothelium,
and pulled back (3 times in each iliac artery). All animals were placed
on a rabbit chow diet (200 g/d) containing 2% cholesterol.
After 6 weeks, angiography was performed to confirm the existence of
iliac lesions. Angioplasty was performed immediately after
angiography.
Rabbits were anesthetized as described above. A 2.5-mm
Bard coronary transluminal balloon angioplasty catheter was
introduced via the carotid artery, and the balloon was positioned under
fluoroscopy at the site of the iliac artery stenosis. Three
successive 1-minute inflations at 6 atm were performed. After
angioplasty, rabbits were again fed the
cholesterol-supplemented diet and were randomized into 2
groups. The active treatment group (L-arg group, n=8)
received 2.25% L-arg hydrochloride (Sigma Chemical Co) in
a limited quantity of drinking water (200 mL) every morning for 4
weeks. The untreated group (n=7) received an equal quantity of plain
drinking water each morning. When the animals had drunk this water,
they were allowed free access to drinking water for the remainder of
the day. The dose of L-arg (2.25%) was chosen based on the
previous studies of Cooke et al,12 who
demonstrated that this dose was well tolerated and resulted in an
increase in plasma free arginine levels compared with controls. Typical
angiographic findings before and after angioplasty and a
histological cross section of iliac artery after
angioplasty are shown in Figure 1
.
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Figure 1. Iliac angiograms before (A) and immediately after
(B) angioplasty. Stenosis that was dilated is indicated by
arrows. After angioplasty, stenosis was significantly less
severe (B). D indicates right side. C, Orcein Van Gieson–stained
photomicrograph of representative
histological section of iliac artery immediately after
angioplasty. Arrow shows intimal dissection. L indicates vessel lumen;
I, intima; EEL, external elastic lamina; M, media; and IEL, internal
elastic lamina. Magnification, x38.
Blood samples were taken at 3 time points (before angioplasty)
in all the rabbits to establish baseline characteristics for the entire
population: at baseline (n=18), at 3 weeks after iliac denudation and
the initiation of a high cholesterol diet (n=18), and at 6
weeks (just before angioplasty) in the surviving rabbits (n=15) (Figure 2). Additional blood samples were taken 4
weeks after angioplasty in the L-arg–treated rabbits (n=8)
and in the untreated rabbits (n=7).
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[in a new window]
Figure 2. Flow chart giving overview of study.
Blood samples were taken under sterile conditions from the ear
artery. Three samples of blood were obtained from each rabbit: 5 mL was
collected in lithium heparin (143 USP units) for mononuclear isolation,
2 mL was collected in sodium citrate (1:10, 3.8%) for plasma
analyses, and 1 mL was collected in EDTA for hematological
analyses (Coulter MAXM). The total white blood cell counts were
verified manually. Peripheral blood smears for the
differential white cell counts were stained with
May-Grünwald-Giemsa. Each count was performed by 3 investigators,
who were blinded to treatment allocation.
The mononuclear cells were isolated by gradient
centrifugation (MSL, density=1.077±0.001,
Eurobio), washed 2 times, and resuspended in RPMI 1640 (GIBCO)
(3x106 cells/mL). Cell viability was >98%
(trypan blue test). Monocytes composed 12±1% (mean±SEM) of the
cells.
The frozen cells were lysed by the addition of 0.05 M
Tris-HCl, 0.1 M NaCl, 0.1% Triton X-100, and 0.1% BSA (60 µL/mL)
for 30 minutes at 37°C with serial vortex mixing. TF activity was
determined with a modified amidolytic assay.24
Briefly, lysed cell suspensions (50 µL) were incubated at 37°C in a
microtiter plate (2 minutes) and mixed with 0.25 M
CaCl2 (50 µL) (3-minute incubation) and
prothrombin concentrate complex (Laboratoire de Fractionnement et des
Biotechnologies) as a source of factor VII (50 µL, 3 UI/mL).
After the addition of 50 µL of the chromogenic substrate
S2765 (Biogenic), the change in optical density at 410 nm was
quantified with a microplate reader and converted to units of TF
activity from log-log plots of serial dilutions of a rabbit brain
thromboplastin (CI+; Stago). Arbitrarily, 1 mL of thromboplastin was
assigned a value of 1000 U/mL TF. Results were expressed as mU/1000
monocytes and as mU of TF/mL of blood.
Immunocytochemical staining was performed on
cytocentrifuged preparations with the use of AP-1 or mouse
negative control (DAKO) and alkaline phosphatase anti-alkaline
phosphatase complex (APAAP Kit system; DAKO). ).
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Figure 3. Representative example of
monocytes with (A) and without (B) qualitative evidence of TF
expression. Magnification, x1250.
Plasma samples were diluted to decrease measurement artifacts
due to severely lipemic plasma.
Results are expressed as mean±SEM. Data were analyzed
using a nonparametric test (Kruskal-Wallis) to determine
significant differences (P<0.05) in mean values between
groups, followed by the Mann-Whitney U test to test the
significance of differences between groups.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Blood Lipid and L-Arg Levels
Serum cholesterol and TG levels were significantly
higher in animals after 6 weeks on a high cholesterol diet
(6 weeks: cholesterol, 3052±278 mg/dL; TG, 489±147 mg/dL;
baseline: cholesterol, 37±3 mg/dL; TG, 108±17 mg/dL;
P<0.004) and remained unchanged 4 weeks after angioplasty,
with no difference between the L-arg group and the
untreated group. The L-arg supplementation
resulted in an increase in plasma arginine level
(315±65 versus 124±11 µmol/L in the untreated
animals, P=0.04).
The total white blood cell count was significantly increased at 6
weeks (just before angioplasty) compared with baseline but did not
differ significantly from baseline at the other time points (Table 1). There were no significant changes in
the levels of circulating monocytes, although the monocyte count was
slightly lower at 3 weeks. A progressive decrease in the platelet
count was observed, with the lowest level observed 4 weeks after
angioplasty.
View this table:
[in a new window]
Table 1. Effect of Hypercholesterolemia, Angioplasty, and
L-Arg on Total White Blood Cell, Monocyte, and Platelet
Counts
Amidolytic activity was detectable in mononuclear cells after a
16-hour culture. Neutralization assay with TF antibody confirmed that
the amidolytic activity was TF in all cases.
In unstimulated cells, a decrease in TF activity was observed 3
weeks after bilateral iliac injury and initiation of the atherogenic
diet (20±3 versus 66±20 mU of TF/1000 monocytes, P=0.02)
and remained lower than the baseline value at all subsequent time
points (Figure 4A).
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Figure 4. Effect of endothelial denudation
and high cholesterol diet on monocyte TF activity. Open
bars indicate mononuclear cells cultured without endotoxin; solid bars,
mononuclear cells cultured with endotoxin (5000 EU/mL). Results are
expressed as mU of TF/103 monocytes (A) or as mU of TF/mL
of blood (B) for baseline (n=18), 3 weeks (n=18), or 6 weeks, just
before angioplasty (n=15). *0.004 
P<0.05 versus
baseline. §0.003P<0.05 versus 3 weeks.
). ).
In unstimulated cells, no significant difference in TF
activity was observed between the group that received L-arg
and the untreated group; TF activity was lower in rabbits with
L-arg, but the difference was not statistically significant
(Figure 5A).
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[in a new window]
Figure 5. Effect of angioplasty and L-arg
supplementation on monocyte TF activity. Open bars indicate mononuclear
cells cultured without endotoxin; solid bars, mononuclear cells
cultured with endotoxin (5000 EU/mL). Results are expressed as mU of
TF/103 monocytes (A) or as mU of TF/mL of blood (B) at 6
weeks, just before angioplasty (preangioplasty, n=15); 4 weeks after
angioplasty without L-arg supplementation (untreated group,
n=7); or 4 weeks after angioplasty with L-arg
supplementation (L-arg group, n=8). $P<0.05
versus 6 weeks. #P<0.05 versus untreated group. ). ).
The results of immunocytochemical staining with anti-TF antibody
in stimulated monocytes were concordant with the results of the
functional TF assays. At baseline, 71% of stimulated monocytes were TF
positive; 63% were TF positive at 3 weeks, and 81% were positive at 6
weeks. At 4 weeks after angioplasty, 92% were TF positive in untreated
animals versus 65% in the L-arg group.
After 3 weeks on a high cholesterol diet, there was a
significant increase in factor II (149±7% versus 94±5% at baseline,
P<0.0001) and factor VII+X (151±7% versus 92±4% at
baseline, P<0.0001), which remained significant at all the
subsequent time points studied. No significant difference in factor V
levels was observed (115±8% versus 103±10% at baseline,
P=NS). Fibrinogen levels were significantly lower after 6
weeks in animals receiving a high cholesterol diet compared
with baseline (2.9±0.3 versus 4.6±0.4 g/L, P=0.0004), and
levels remained at this level 4 weeks after angioplasty (2.4±0.3
g/L). ).
View this table:
[in a new window]
Table 2. Factors II, V, and VII Plus X and Fibrinogen Levels
in Untreated and L-Arg Groups
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The major finding of this study was the demonstration that
the performance of angioplasty in a rabbit model of
atherosclerosis induced by a high
cholesterol diet and iliac denudation is associated with a
significant increase in monocyte TF response, which is blunted by
dietary L-arg supplementation. This is the first study to
investigate monocyte TF responses in vivo in a rabbit model of induced
atherosclerosis and to study the effect of the NO
precursor L-arg in this model.
We observed a decrease in monocyte TF activity in the weeks after
initiation of a high cholesterol diet associated with
bilateral iliac injury. The reasons for this decrease are unclear, but
they could be related to the disappearance from the bloodstream of the
most active monocytes; this hypothesis is supported by the observation
that the monocyte count tended to decrease over the same period. This
may reflect an increase in monocyte adhesion and penetration into the
vascular wall.1 25 Alternatively,
hypercholesterolemia could modify the lipidic
composition of cell membranes, modulating TF activity, or it increase
the specific TF pathway inhibitor, as previously shown in
humans.26
At 4 weeks after angioplasty, we observed an increased monocyte TF
response to endotoxin. This probably reflects an increase in the degree
of activation of circulating monocytes, as already described in human
coronary disease, specifically in unstable coronary
syndromes.3 4 Leukocyte activation has been
described in the early days after coronary angioplasty in
humans,29 but no previous study has investigated
leukocyte activation several weeks after balloon injury. A potential
hypothesis is that the rupture of lipid-rich
atheromatous plaque by angioplasty allows direct
contact between the plaque components, including foam cells,
activated T cells, and activated
macrophages, which could produce inflammatory
cytokines and activate the TF
gene.30 This hypothesis is supported by the
observation that animals that received a high cholesterol
diet over an equivalent time period but were not subjected to iliac
denudation did not have demonstrable changes in levels of TF response
(data not shown), as previously reported.31
Dietary L-arg supplementation had a significant effect
on monocyte TF response. The increase in stimulated monocyte TF
response that occurred in untreated animals was significantly blunted
by oral administration of L-arg. The mechanisms of the
inhibitory effect of L-arg on monocyte TF
activity are unclear. This effect could be related to the
antiatherogenic effect of L-arg: it has been demonstrated
that hypercholesterolemia increases the
generation of superoxide anion in endothelial cells,
which plays a key role in the pathogenesis of
atherosclerosis,32 33 and this
process is limited by L-arg
supplementation.12 19 B or scavenge the
superoxide anion that activates
NF-B.15 16 18 34 Because TF gene activation by
endotoxin is mediated by NF-B activation, the modulation by NO of
monocyte TF response in our model could occur through limitation of
this common oxidant-sensitive transcriptional pathway. Indeed, recent
data indicate that an antioxidant phytoelement can inhibit
cytokine-induced TF gene expression in part through
inhibition of NF-B activation in cultured
endothelial cells.35 To our
knowledge, the effect of NO on monocyte TF response had not previously
been studied. Alternatively, Brisseau et al36
demonstrated in vitro that antioxidants decreased TF expression by
monocytes/macrophages through a post-transcriptional effect.
These elements combined suggest that NO may reduce monocyte TF response
through direct transcriptional or post-transcriptional mechanisms.
Monocyte TF mRNA determination will provide further insights into the
relative contribution of these two possible mechanisms.
The extrapolation of data from any animal model to human
atherosclerosis requires caution. However, the
atherosclerotic rabbit model we used has been demonstrated to have
several features in common with human atherosclerosis,
and its reproducibility has been demonstrated in several previous
studies.23 37 A diet supplemented with 2%
cholesterol results in very high cholesterol
levels in this model and severe atherosclerotic lesions and is
associated with significant morbidity rates in the animals. The results
of the present study might differ in animals with lesser degrees of
cholesterol supplementation. Similarly, stimulation with
endotoxin may not reflect the pathophysiological
changes seen in atherosclerosis; however, it is a
powerful stimulator of TF gene, and infectious agents are possible
aggravating factors in the evolution of
atherosclerosis.38
Acknowledgments
This work was supported by grants from the Direction de la
Recherche et des Etudes Doctorales (EA 1044), the Centre Hospitalier et
Universitaire de Lille (grant 96/35/9506), and Région Nord-Pas de
Calais France. Dr Corseaux was a recipient of a 2-year doctoral grant
from CHRU Lille and Région Nord Pas de Calais. We thank the
Laboratory of Biochemistry of Pr Formstecher (CHRU de Lille) for
assistance with the measurement of plasma cholesterol and
TG. We thank the Laboratory of Anatomocytology of Pr Gosselin (CHRU de
Lille) for tissue preparations.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
B. Thromb Haemost. 1997;77:772–782.[Medline]
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