(Circulation. 1997;95:1532-1541.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin-Converting Enzyme Inhibition Prevents Arterial Nuclear Factor-
B Activation, Monocyte Chemoattractant Protein-1 Expression, and Macrophage Infiltration in a Rabbit Model of Early Accelerated Atherosclerosis
From the Research Laboratory (M.H.-P., C.B., M.O., M.R.-O., J.E.), Division of Cardiology (J.T.), and Department of Pathology (G.R.), Fundación Jiménez Díaz, Autonoma University, Madrid, Spain.
Correspondence to Jesús Egido, MD, Research Laboratories, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain. E-mail egido{at}alpha2.ft.uam.es
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background The migration of monocytes into the vessel wall is a critical event leading to the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is the main chemotactic factor involved in this phenomenon, and nuclear factor-
B (NF-B)
is one of the nuclear factors controlling its expression. ACE
inhibitors have been useful in some experimental models of
atherosclerosis. In this work, we addressed the hypothesis that
angiotensin II (Ang II) may be implicated in the recruitment of
monocytes into the vessel wall through the activation of NF-B and
the induction of MCP-1 expression.
Methods and Results Accelerated atherosclerosis was induced
in the femoral arteries of rabbits by endothelial desiccation and
atherogenic diet for 7 days. Atherosclerotic vessels exhibited an
increase in NF-B–like activity, and p50 and p65 NF-B subunits
were identified as components of this activity. MCP-1 (mRNA and
protein) was also expressed in the injured vessels coincidently with
the neointimal macrophage infiltration. ACE inhibition with quinapril
reduced these three parameters. In cultured monocytic and vascular
smooth muscle cells, Ang II elicited an increase in NF-B activation
and MCP-1 expression that was prevented by preincubation of cells with
pyrrolidinedithiocarbamate, an inhibitor of NF-B activation.
Conclusions The present data support a role for Ang II in
neointimal monocyte infiltration through NF-B activation and MCP-1
expression in a model of accelerated atherosclerosis in rabbits. Our
results suggest that ACE inhibitors may have a beneficial effect in
early atherosclerosis.
Key Words: angiotensin • atherosclerosis • molecular biology • immunohistochemistry
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The migration of monocytes into the subendothelial space of the vessel wall is an early event in the development of the atherosclerotic plaque.1 MCP-1, the main chemotactic factor involved in this process, is expressed in response to several stimuli both in vitro (LDL, IL-1, TNF-
, interferon-
, macrophage colony–stimulating
factor2 ) and in vivo (hypercholesterolemia3
and balloon injury4 ). During vascular injury, MCP-1 is
expressed mainly by macrophages but also by endothelial cells and
VSMCs.5
Within the human MCP-1 gene promoter region, two cis-acting
elements have been identified: a remote B region responsible for the
induction of transcription after stimulation and a GC box (SP1 binding
site) responsible for the maintenance of low levels of basal
transcription.6 NF-B is the main factor involved in the
transcription of MCP-1 induced by LPS, IL-1ß, TNF-, and phorbol
esters.6 The implication of NF-B activation in the
pathogenesis of atherosclerosis is an attractive emerging idea. The
proliferation of VSMCs in response to thrombin is mediated by
NF-B.7 Moreover, vascular endothelial cells respond to
oxidative stress with NF-B activation and adhesion molecule
generation.8
Recent data suggest that the renin-angiotensin system may play an important role in the pathogenesis of atherosclerosis. In humans, an upregulation of ACE was associated with an enhanced risk of myocardial infarction,9 and ACE inhibitors seem to reduce the incidence of reinfarction.10 Although several potential mechanisms of these effects, including plaque stabilization, have been proposed,11 there is not yet any clear explanation. In animal models, ACE inhibitors induced a reduction in neointima formation after vascular injury,12 and a beneficial effect in restenosis has been suggested.13 However, until now, clinical trials have failed to support this hypothesis.
A growing body of evidence indicates that Ang II affects circulating
cells. Ang II receptors have been demonstrated on human
monocytes.14 Moreover, Ang II stimulates chemotaxis of
human mononuclear cells.15 Therefore, in this article we
explore the hypothesis that Ang II could be responsible, at least in
part, for the macrophage accumulation in the damaged artery. Overall,
we have shown that during early accelerated atherosclerosis in rabbits,
there is an increase in arterial NF-B–like activity composed of at
least p50 and p65. MCP-1 gene and protein expression was also increased
in temporal correlation with macrophage infiltration of the neointima.
Administration of the ACE inhibitor quinapril prevented the increase of
NF-B activity and MCP-1 expression and reduced the mononuclear cell
infiltration of vessels. In cultured VSMCs and macrophages, Ang II
elicited an upregulation of the MCP-1 gene and NF-B activation. Our
results clearly implicate Ang II as a new mediator of macrophage
recruitment into vessel wall in a model of accelerated
atherosclerosis.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Induction of Focal Atherosclerosis
Atherosclerosis was induced according to a previously described technique, with minimal modifications.16 Male New Zealand White rabbits were anesthetized by intramuscular injection of 5 mg/kg xylazine (Rompun, Bayer AG) and 35 mg/kg ketamine (Ketolar, Parke-Davis). Local relief of pain was achieved by subcutaneous injection of 2% lidocaine (Braun). A prophylactic intramuscular injection of 125 mg/kg cefazoline (Llorente Laboratories) was administered 30 minutes before the surgical procedure; all the techniques were done under sterile conditions. Blood (10 mL) was drawn from the ear vein for biochemical studies and serum ACE activity measurement. Arterial pressure was estimated by sphygmomanometer in the femoral artery. Proximal bilateral femoral arteriotomies were performed, and proximal and distal ligatures were placed to isolate a segment of
20 mm, which was cannulated with a 27-gauge needle.
A vent was made by needle puncture, and blood was removed by a flush of
saline. Endothelial damage was induced by the passage of industrial
nitrogen at a rate of 80 mL/min for 8 minutes. The isolated segments
were then flushed again with saline, and the ligatures were removed.
Hemostasis was achieved by local pressure, and the wound was closed
with a 4.0 vicryl subcuticular suture. Two days before the surgical
procedure, the animals were randomized to quinapril (Parke-Davis) or no
treatment. Quinapril was freshly dissolved every other day in the
drinking water and given to the rabbits at 1
mg·kg-1·d-1.
The consumption of water was measured every other day to confirm the
appropriate administration of the drug. After the surgical procedure,
the animals were given a 2% cholesterol/6% peanut oil diet (Letica)
and maintained for 7 days in individual cages. We used 20 animals
weighing 3.5 to 4 kg (mean, 3617±223 g) for mRNA expression and
immunohistochemistry. Eight were untreated, 8 were treated with
quinapril, and 4 were controls (fed standard chow and with no
experimental intervention). Six more (3 treated and 3 untreated) were
used for NF-B determination. Five additional animals were killed
after 2 days of quinapril consumption with no surgical intervention to
quantify vascular ACE activity.
Harvesting of Vessels
At the time they were killed, animals were anesthetized with
ketamine/xylazine, and 10 mL blood was drawn from the ear vein for
biochemical determinations. Both femoral arteries were exposed, and
ligatures were placed to isolate the damaged segments and flushed with
saline. One of the arteries was removed, the adventitial layer was
carefully peeled off, and the artery was immediately snap-frozen in
liquid nitrogen. The aorta was ligated, flushed with saline, removed,
and also snap-frozen in liquid nitrogen. The animals were euthanatized
with an overdose of pentobarbital (Abbot), and the other femoral artery
was cannulated and fixed in situ with 100 mL 4% buffered formaldehyde
at 100 mm Hg pressure. Then it was removed and kept for 24 hours
in the same buffer and after that in 70% ethanol until it was embedded
in paraffin.
Measurement of ACE Activity and Serum Cholesterol
ACE activity determinations were done in serum and in samples of
frozen uninjured artery (aorta) as previously described.17
Artery samples were homogenized in 0.05 mol/L HEPES, 0.1 mol/L NaCl,
and 0.05% Triton X-100, pH 7.5, and centrifuged at 12 000g
for 10 minutes at 4°C. The resulting supernatant was used for
analysis of tissue ACE activity.
Serum cholesterol was measured by standard techniques and with an enzymatic kit (Biomerieux).
Immunohistochemistry
Paraffin-embedded arteries were cross-sectioned into pieces
4 µm thick at 5-mm intervals from the proximal to the distal
end, dewaxed, and rehydrated. Macrophages were identified with a
monoclonal antibody for rabbit macrophages (anti–RAM-11,
DAKO).18 MCP-1 was detected with a polyclonal goat
anti-human MCP-1 antibody (Immunogenex Corp). Endogenous peroxidase
activity in the sections was quenched by incubation in 3% hydrogen
peroxide:methanol (1:1) for 30 minutes. Nonspecific antibody binding
was blocked by incubation of the tissue section for 1 hour in
suppressor serum consisting of 6% goat serum and 4% BSA in PBS (pH 7)
for RAM-11 and 6% horse serum and 4% BSA in PBS (pH 7) for
anti–MCP-1. RAM-11 (84 µg/mL in 1% goat serum and 4% BSA in PBS)
was applied for 1 hour, and anti–MCP-1 (70 µg/mL in 1% horse serum
and 4% BSA in PBS) was applied overnight. Secondary antibodies (goat
anti-mouse IgG HRPO-conjugated [Seralab] for RAM-11 and donkey
anti-goat IgG HRPO-conjugated [The Binding Site] for anti–MCP-1)
diluted 1:100 in 4% BSA were applied for 30 minutes, then sections
were stained for 10 minutes at room temperature with 0.05%
3,3'-diaminobenzidine tetrahydrocloride (DAKO) and 0.01% hydrogen
peroxide in PBS. Finally, sections were counterstained with hematoxylin
and mounted in Pertex (Medite). In each experiment, negative controls
without the primary antibody or with an unrelated antibody were
included to check for nonspecific staining.
For quantification, the sections with the maximal lesion in each animal were chosen. Computer-assisted morphometric analysis was performed with the Cue-2 semiautomatic image analysis system (Olympus). The arterial cross sections stained with the antibodies were digitized with an Olympus microscope (BH-2) connected to a CCD video camera and to the Cue-2 image analysis system. After image acquisition, a gray value ranging from 0 to 255 was assigned to each pixel. The labeled areas in the intima and the media were delimited, and after image enhancement (converting near-white pixels to white and near-black pixels to black and stretching the remaining pixels uniformly over the ranges of gray-level values) and segmentation (transformation of image into a binary image) to set a threshold value, automatic analysis was performed. Results were expressed as inmunostained area and fractional area of intima and media.
Morphometric Analysis
The morphometric analysis was performed with the NewSketch
1212 graphic tablet (Genius) linked to a microcomputer. Sections with
the maximal lesion were chosen for quantification. The area was
obtained by tracing the perimeters of the lumen and the internal and
external elastic laminae.
Cell Culture
Smooth muscle cells. Rat thoracic aortic VSMCs were
isolated and cultured by a modification of the method of Owens et
al.19 Briefly, adhering fat and connective tissue were
removed by blunt dissection from the thoracic aorta. Vessels were
opened longitudinally and preincubated in DMEM (Whitaker) containing 1
mg/mL collagenase (type II, 290 U/mg), penicillin (100 U/mL),
streptomycin (100 µg/mL), and glutamine (2 mmol/L) (Sigma) for
15 to 20 minutes at 37°C in 95% air/5% CO2. Then aortas
were minced into 1-mm pieces, incubated for an additional 1.5 to 2
hours, and rinsed twice with PBS to remove the cells, which were
counted and seeded at a concentration of 104
cells/cm2 in plastic culture flasks (Costar). Cells were
harvested for passaging at 2-week intervals and used between the 2nd
and 10th passages.
U937 cell line. U937 cells (human monocytic cell line) were obtained from the American Type Culture Collection (1593-CRL) and were cultured in RPMI medium (Whitaker) with 10% FCS.
RNA Extraction and Northern Blot Analysis
U937 and VSMCs were growth-arrested by incubation in 0.5% FCS
medium for 24 hours and then incubated with the corresponding stimuli.
Frozen femoral arteries were pulverized in a metallic chamber. RNA was
obtained by the acid guanidinium thiocyanate–phenol-chloroform
method20 and quantified by absorbance at 260 nm in
duplicate. RNA (5 µg) from each animal of every group was pooled, and
20 µg of the pool and 30 µg of RNA from the cells were denatured
and electrophoresed in a 1% agarose-formaldehyde gel, transferred to
nylon membranes (Genescreen, New England Nuclear), and fixed by
exposure to UV light for 3 minutes and baking at 80°C for 90 minutes.
The membranes were prehybridized for at least 4 hours at 42°C in 50%
formamide, 1% SDS, 5xSSC, 5xDenhardt's solution, 0.1 mg/mL
denatured salmon sperm DNA, and 50 mmol/L sodium phosphate buffer,
pH 6.5. Hybridization was carried out at 42°C overnight with 20%
dextran sulfate and [-32P]-labeled denatured probe.
The membranes were washed with 2xSSC, 0.1% SDS for 30 minutes at room
temperature and then with 0.2x SSC, 0.1% SDS at 55°C for 15
minutes. Autoradiography was performed by standard methods. The cDNA
probes for human MCP-1 (JE*/pGEM-hJE34) and 28S rRNA (HHCD07) were
obtained from the American Type Culture Collection. Human MCP-1 probe
was checked for hybridization with rat mRNA and used for hybridization
both with human U937 cells and with rat VSMCs. The rabbit MCP-1 probe
was obtained from the PCR product as explained below. Films were
scanned by the Image Quant densitometer (Molecular Dynamics). 28S
ribosomal RNA or ethidium bromide staining was used as internal
control.
Reverse Transcription and Semiquantitative PCR Analysis
RNA (1 µg) from each animal was reverse transcribed to
single-stranded cDNA by incubation with 20 µL reverse transcription
mixture (5 mmol/L MgCl2, 10 mmol/L Tris-HCl [pH
8.8], 50 mmol/L KCl, 0.1% Triton X-100, 1 mmol/L dNTP
mixture, 20 U rRNAsin [ribonuclease inhibitor], 15 U avian
myeloblastosis virus reverse transcriptase, and 50 ng oligo dT) at
42°C for 30 minutes according to the manufacturer's instructions
(Promega). PCR was conducted in the presence of
[-32P]dCTP for 25, 30, 35, and 40 cycles in the same
conditions for MCP-1 and GAPDH, used as internal control (1 minute at
54°C to allow annealing of the primers, 3 minutes at 72°C for
primer extension, and 1 minute at 94°C to denature the
double-stranded DNA). The following primers were used for rabbit
MCP-121 : sense, 5'-TGTGCTTGCCCAGCCAGATG-3' and
antisense, 5'-GTGTCTGCATTTTCTTGTCC3', which yielded a product of 230
bp. For GAPDH22 : sense, 5'-AATGCATCCTGCACCACCAA-3' and
antisense, 5'-ATACTGTTACTTATACCGATG-3', which yielded a product of 515
bp. The DNA products from the PCR reactions were analyzed on a 4%
polyacrylamide/urea gel in TBE buffer. The polyacrylamide gels were
dried, exposed to x-ray films, and scanned with the IQ
densitometer.
Protein Extraction
From tissue. For protein extraction from tissue
samples, the method of Negoro et al23 was used, with
modifications. Briefly, frozen arterial pieces were pulverized in a
metallic chamber and resuspended in 1 mL cold extraction buffer
containing 20 mmol/L HEPES-NaOH (pH 7.6), 20% (vol/vol) glycerol,
0.35 mol/L NaCl, 5 mmol/L MgCl2, 0.1 mmol/L EDTA,
1 mmol/L DTT, 0.5 mmol/L PMSF, and 1 µg/mL pepstatin A. The
homogenate was vigorously shaken for 30 minutes, insoluble materials
were precipitated by centrifugation at 40 000g for 30
minutes at 4°C, and the supernatant was dialyzed overnight against a
binding buffer containing 20 mmol/L HEPES-NaOH (pH 7.6), 20%
(vol/vol) glycerol, 0.1 mol/L NaCl, 5 mmol/L MgCl2,
0.1 mmol/L EDTA, 1 mmol/L DTT, and 0.5 mmol/L PMSF. The
dialysate was cleared by centrifugation at 10 000g for 15
minutes at 4°C and frozen at -80°C in aliquots until use. Protein
concentration was quantified by the BCA method.
From cells. Cells were made quiescent for 24 hours in 0.5% FCS medium, and then 5x106 cells were incubated with the stimuli for different periods of time. Cells were collected, washed with cold PBS, and resuspended in 5 cell-pellet vol buffer A (in mmol/L: HEPES 10 [pH 7.8], KCl 15, MgCl2 2, EDTA 0.1, DTT 1, and PMSF 1). After 10 minutes on ice, the cells were pelleted, resuspended in 2 vol buffer A, and homogenized. Nuclei were centrifuged at 1000g for 10 minutes, washed twice in buffer A, and resuspended in 2 vol buffer A. Then 3 mol/L KCl was added drop by drop to reach 0.39 mol/L KCl. Nuclei were extracted for 1 hour at 4°C and centrifuged at 100 000g for 30 minutes. Supernatant was dialyzed in buffer C (mmol/L: HEPES 50 [pH 7.8], KCl 50, PMSF 1, EDTA 0.1, and DTT 1, and 10% glycerol) and then cleared by centrifugation and stored at -80°C. Protein concentration was determined by the BCA method.
Electrophoretic Mobility Shift Assays
Gel shift assays were performed with a commercial kit according
to the instructions of the manufacturer (Promega). Briefly, NF-B
consensus oligonucleotide (5'-AGTTGAGGGGACTTTCCCAGGC-3') was
[32P]-end-labeled by incubation for 10 minutes at 37°C
with 10 U T4 polynucleotide kinase (Promega) in a reaction containing
10 µCi [-32P]ATP (3000 Ci/mmol) (Amersham), 70
mmol/L Tris-HCl, 10 mmol/L MgCl2, and 5 mmol/L
DTT. The reaction was stopped by the addition of EDTA to a final
concentration of 0.05 mol/L. Nuclear or cellular protein (10 µg) was
equilibrated for 10 minutes in a binding buffer containing 4%
glycerol, 1 mmol/L MgCl2, 0.5 mmol/L EDTA,
0.5 mmol/L DTT, 50 mmol/L NaCl, 10 mmol/L Tris-HCl (pH
7.5), and 50 µg/mL poly(dI-dC) (Pharmacia LKB). When competition
assays were performed, the cold probe was added to this buffer 10
minutes before the addition of the labeled probe. Labeled probe (0.35
pmol) was added to the reaction and incubated for 20 minutes at room
temperature. For supershift assays, 1 µg anti-p65 (Santa Cruz
Biotechnology Inc) or anti-p50 (Chemikon) antibody was added and
incubated for 1 hour. The reaction was stopped by addition of gel
loading buffer (250 mmol/L Tris-HCl, 0.2% bromophenol blue, 0.2%
xylene cyanol, and 40% glycerol) and run on a nondenaturing, 4%
acrylamide gel at 100 V at room temperature in TBE. The gel was dried
and exposed to x-ray film.
Statistical Analysis
Results are expressed as mean±SD (unless specified).
Significance was established with GraphPAD InStat (GraphPAD Software).
Student's t test and Wilcoxon's nonparametric test were
used to compare the data. Differences were considered significant when
P<.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Biochemical Parameters
Total serum cholesterol of rabbits on a high-fat diet for 7 days increased 10-fold over the basal values of the same animals before they started the diet (643±343 versus 60±24 mg/dL).
Measurement of ACE Activity
Quinapril (1
mg·kg-1·d-1)
was administered to the animals from 2 days before the induction of the
focal atherosclerosis (day -2) until they were killed. At the moment
of injury (day 0), there was a significant diminution in serum ACE
activity (2.5±0.9x10-2 versus
8.5±3x10-2 U/mL, P<.008) and in
arterial blood pressure (61±16 versus 83±12 mm Hg,
P<.0001). However, at this time there was no significant
change between vascular ACE activity (determined in the aorta) in
quinapril-treated and control rabbits
(1.2±0.2x10-2 U/mg, n=5, versus
1.1±0.4x10-2 U/mg, n=4). At death (day 7),
serum ACE activity could not be quantified because of the turbidity
caused by the hyperlipidemia. Vascular ACE activity, however,
diminished 40% in quinapril-treated versus nontreated rabbits.
Immunohistochemistry and Morphological Analysis
Injured arteries were paraffin-embedded, and serial sections were
stained with the RAM-11 or the anti–MCP-1 antibody. As shown in Fig 1
(bottom photomicrographs), no control (healthy) animal
showed any stain with the antibodies. Untreated animals presented a
marked stain with the anti–MCP-1 antibody coinciding with a certain
number of macrophages in the incipient neointima (Fig 1, top). By
contrast, quinapril treatment (Fig 1, middle) was associated with a
significant diminution of macrophage infiltration (17±16 versus
4897±2998 µm2, P<.03) and MCP-1
staining (3378±693 versus 8809±2585 µm2,
P<.02), Fig 1, graph. No significative changes were noted
in the mild neointima formation, although a certain trend toward
normalization was found in the quinapril-treated group (intima/media
ratio: 0.125±0.024 versus 0.165±0.03, P=.3; maximal
lesion: 28 770±4746 versus 45 859±9372 µm2,
P=.15). No staining was observed in the negative controls
included in each experiment (not shown).
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MCP-1 Gene Expression in Injured Femoral Arteries
Because of the small amount of RNA obtained from each arterial
sample, MCP-1 mRNA expression was studied in each individual artery by
a semiquantitative PCR method by amplifying a fragment of MCP-1 in the
same conditions as a fragment of the housekeeping gene GAPDH, as
described in "Methods." Densitometry of the bands obtained after
the electrophoresis of the PCR products in polyacrylamide/urea gels
showed that the amplification was linear up to 35 cycles both for MCP-1
and for GAPDH, and data for cycle 35 were used for calculations.
Control animals showed no detectable expression of MCP-1, whereas this
was significantly increased in untreated animals (6.3±1.2 AU; n=6).
Quinapril-treated rabbits showed a significant diminution in arterial
MCP-1 expression (3.4±1.4 AU; n=7; P<.04 versus untreated
animals). A representative PCR obtained after pooling of 1 µg RNA
from each animal in every study group is shown in Fig 2.
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indicates GAPDH (G3PHD);
, MCP-1. Right side shows autoradiography of dried gels. Right,
Northern blot analysis of MCP-1 mRNA expression in femoral arteries of
(1) control, (2) untreated, and (3) quinapril-treated rabbits. RNA from
animals of same group was pooled, and Northern blot was carried out
with 32P-radiolabeled probe for rabbit MCP-1 obtained from
PCR ("Methods"). Middle panel shows ethidium bromide staining of
gel. Bottom, densitometric analysis.
Similar results (50% reduction in MCP-1 mRNA expression in the
quinapril-treated group) were obtained when a pool of RNA from every
experimental group was subjected to Northern blot analysis (Fig 2
).
NF-B Activity in Arteries of Rabbits
Both injured femoral arteries of three different animals from each
group (controls, untreated, and quinapril-treated) were removed, and
cellular extracts were pooled. NF-B activity was quantified in 10
µg total protein from each pool, and experiments were done in
duplicate. Negative control experiments without cellular extracts and
competition assays with a 50-fold excess of cold NF-B and cold AP-1
oligonucleotides were performed to establish the specificity of the
reaction. No signal was found in the reactions without cellular
extracts, and the reaction was proved to be specific because cold
NF-B but not cold AP-1 decreased the signal of the retarded bands
(not shown). In relation to controls, injured arteries from untreated
animals showed a 7-fold increase in NF-B activity that decreased to
a 4-fold increase in quinapril-treated animals (Fig 3).
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Supershift assays with the cellular extracts obtained from the
untreated animals were performed to characterize the NF-B activity
found in the arteries. Both the anti-p65 and anti-p50 antibodies
reduced the intensity of the major band. In addition, the anti-p50
antibody induced the appearance of a supershifted complex. Therefore,
p65 and p50 seem to be components of the NF-B activity found in the
artery wall.
MCP-1 Gene Expression in Monocytes and in VSMCs
Macrophages are primarily responsible for the increase in MCP-1 in
atherosclerotic arteries,5 although VSMCs can also
synthesize this chemokine. To show the effect of Ang II on MCP-1
expression, some experiments with cultured U937 cells and VSMCs were
done. In preliminary studies, maximal MCP-1 expression was found at 6
hours of incubation in both mononuclear and vascular cells (data not
shown). In subsequent experiments, growth-arrested cells were incubated
for 6 hours in 0.5% FCS medium with Ang II
(10-7, 10-9, and
10-10 mol/L). In U937 cells, Ang II
(10-9 mol/L) elicited a 3-fold and TNF-
(positive control) a 6-fold increase in MCP-1 mRNA expression (Fig 4A). MCP-1 gene expression in VSMCs was also triggered
by Ang II, with a similar dose-response curve (Fig 4B).
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To analyze whether NF-B mobilization could be involved in
MCP-1 activation induced by Ang II, cells were preincubated for 1.5
hours with 200 µmol/L PDTC (Sigma), a substance that has been
described as inhibiting NF-B activation in several cell
types.24 In all experiments, MCP-1 expression was blocked
by preincubation with PDTC, suggesting that the increased MCP-1 mRNA
expression elicited by Ang II was mediated by NF-B activation in
mononuclear cells and VSMCs (Fig 4).
NF-B Activation in Monocytes and in VSMCs
Growth-arrested U937 cells were incubated with Ang II
(10-7, 10-9, and
10-10 mol/L) for 30, 60, and 120 minutes,
nuclear extracts were obtained, and the amount of active NF-B was
estimated by gel-shift assay. Optimal induction was found after 1 hour
of stimulation, returning almost to basal levels at 2 hours. All
subsequent experiments were done at 1 hour. The specificity of the
reaction was established according to the same controls as described
above. Ang II augmented NF-B activity, being maximal at
10-9 mol/L (3-fold over basal). LPS, a strong
inducer of NF-B activation in macrophages, was used as positive
control (Fig 5). Preincubation of the cells with PDTC
abolished NF-B activation (not shown). Preincubation of the nuclear
extracts for 1 hour with 1 µg anti-p50 or anti-p65 antibodies reduced
the intensity of the bands, and anti-p50 antibody induced the
appearance of a supershifted band.
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The ability of Ang II to induce NF-B activation in VSMCs was also
assessed. As can be seen in Fig 6, Ang II increased
NF-B activation with a time course and dose response similar to that
in monocytic cells: 10-9 mol/L Ang II induced
a 7-fold increase. NF-B activation was abolished by preincubation of
cells with 200 µmol/L PDTC for 1.5 hours. Preincubation of the
cells with anti-p50 for 1 hour reduced the intensity of the main band,
and anti-p65 almost abolished it (Fig 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this article, we show that in rabbits with early accelerated atherosclerosis, the administration of low doses of the ACE inhibitor quinapril decreased NF-
B activity, MCP-1 expression, and macrophage
accumulation in the endothelium-injured arteries. In cultured
mononuclear cells and VSMCs, Ang II elicited an upregulation of MCP-1
gene expression, probably through the activation of NF-B. Since in
human atheromatous lesions, the concentration of macrophages is great
in fissured and ulcerated plaques,25 26 this effect of
quinapril could contribute to the stabilization of the atherosclerotic
plaque.
Ang II Participates in the Macrophage Recruitment Into the
Neointima
In intact vessels, ACE activity is generated mainly by endothelial
cells, whereas during the atherosclerotic process, the VSMCs from the
neointima became the agent primarily responsible for the observed
increase in ACE activity.13 The fact that both ACE
inhibitors and type 1 Ang II receptor antagonists reduce neointimal
proliferation suggests that Ang II may be directly implicated in this
phenomenon.27 According to the present results, Ang II
triggers the generation of MCP-1 by both mononuclear cells and VSMCs
and could therefore participate in monocyte recruitment into the
atherosclerotic lesion. The chemotactic activity of Ang II and its
degradation products on mononuclear cells is well
established.15 Ang II can also induce the generation of
neutrophil chemoattractants by endothelial cells.28 We
have observed that the administration of quinapril to animals with
endothelial damage and atherogenic diet decreases MCP-1 expression and
the number of macrophages invading the neointima. This effect could be
due to the reduction in Ang II induced by quinapril and is supported by
the in vitro studies in which Ang II directly elicited the gene
expression of MCP-1.
However, ACE inhibitors also modify the generation of NO, and this
could be another pathway by which these drugs could have a beneficial
effect in reducing mononuclear cell accumulation. In endothelial cells,
a diminution in the basal production of NO can induce an increase of
MCP-1 production and NF-B activity.29 Ang II can
downregulate the expression of the inducible NO synthase triggered by
cytokines.30 In a situation of vascular damage with
increased cytokine levels, the blockade of Ang II generation could
contribute to abolishing this negative effect of Ang II on NO
generation.
Ang II Triggers MCP-1 mRNA Expression Via NF-B Activation in
Cultured Macrophages and VSMCs
Our results also show that the increase in MCP-1 expression
induced by Ang II is mediated by the activation of NF-B. The
mechanisms by which Ang II triggers NF-B activation are not
completely elucidated. Although the pathway of activation of NF-B is
multifactorial, a serine-threonine protein kinase seems to be
involved.31 In different cells such as VSMCs, Ang II
increases protein tyrosine phosphorylation and activates several
protein kinases, including protein kinase C.32 33 However,
there is no direct evidence that this kinase plays any role in NF-B
mobilization. Ang II also phosphorylates the STAT family of
transcription factors through the activation of type 1 Ang II
receptor.34 Stat3-related protein is elicited by the
Src oncogene tyrosine kinase,35 which is
activated in VSMCs after stimulation with Ang II.36
Several lines of evidence indicate that reactive oxygen intermediates,
in particular H2O2, serve as messengers in the
activation pathway of NF-B.37 In fact, radical
scavengers such as PDTC decrease NF-B activation and the gene
expression of MCP-1 and other inflammatory genes.38 Recent
data have shown that reactive oxygen intermediates also seem to be
involved in the intracellular transduction of Ang II
signal.39 Our data showing PDTC abrogation of Ang II
effects are in agreement with this mechanism.
ACE Inhibition Decreases NF-B Activation in Injured
Vessels
Although previous studies had shown that in hyperlipidemic
hamsters, the ACE inhibitor captopril inhibited macrophage–foam cell
accumulation independently of blood pressure and plasma lipids, no
possible explanations were approached.40 In this article,
we demonstrate that the diminution of monocytes in the neointima of
hyperlipidemic rabbits treated with quinapril was clearly linked to the
reduction both in NF-B activation and in MCP-1 mRNA and protein
expression in the arterial wall. These findings are in agreement with
the idea that activation of NF-B and the subsequent expression of
inflammatory genes are leading events in the development of
atherosclerosis. NF-B activity can be induced in a wide variety of
cell types in response to treatment with agents such as IL-1, TNF-,
adhesion, oxidative stress, and oxidized LDL.41 In this
study, we also show that Ang II is another factor that could be added
to this list. Interestingly, constitutive NF-B activity is essential
for proliferation of cultured bovine VSMCs.42 Therefore,
ACE inhibitors could modify vascular injury, modulating both the
mononuclear cell infiltration and the proliferation of VSMCs.
Recent data have shown that the instability of the atherosclerotic plaque is closely related to its macrophage content.25 One could speculate that during early atherosclerosis in rabbits, the diminution in MCP-1 production and macrophage content in the neointima induced by quinapril could favor the stabilization of the lesion. In this sense, a diminution in the risk of acute ischemic events in patients receiving ACE inhibitors has been pointed out previously.10
Overall, the present data show that during early accelerated
atherosclerosis in rabbits, there was an increase in NF-B
activation, MCP-1 expression (gene and protein), and macrophage
accumulation in the artery wall that was prevented by quinapril
treatment. Ang II increased MCP-1 mRNA expression and NF-B
activation in cultured mononuclear cells and VSMCs. The present
experiments and those of previous authors suggest that Ang II is
emerging as an important regulator of two important phenomena of
atherosclerotic plaque formation, such as macrophage accumulation and
VSMC proliferation. Our results support the idea that ACE inhibitors
might have a beneficial effect in the earliest phases of
atherosclerosis.
|
Selected Abbreviations and Acronyms |
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Acknowledgments |
|---|
This work was supported by grants from FISS (93/5389, 94/0370), Ministerio de Educación y Ciencia (MEC) (PB 94/0211), and Fundación Iñigo Alvarez de Toledo. M. Hernández-Presa is a fellow of MEC. The authors want to thank Dr C. Gómez-Guerrero and Dr C. Guijarro for helpful revision and comments on the manuscript and Dr S.L. Sarasa for technical help with the photographs.
Received August 26, 1996; accepted October 20, 1996.
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References |
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 K. Sekiguchi, X. Li, M. Coker, M. Flesch, P. M Barger, N. Sivasubramanian, and D. L Mann Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure Cardiovasc Res, August 15, 2004; 63(3): 433 - 442. [Abstract] [Full Text] [PDF]
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A. Alvarez, M. Cerda-Nicolas, Y. Naim Abu Nabah, M. Mata, A. C. Issekutz, J. Panes, R. R. Lobb, and M.-J. Sanz Direct evidence of leukocyte adhesion in arterioles by angiotensin II Blood, July 15, 2004; 104(2): 402 - 408. [Abstract] [Full Text] [PDF]
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K. Tsunemi, S. Takai, M. Nishimoto, D. Jin, M. Sakaguchi, M. Muramatsu, A. Yuda, S. Sasaki, and M. Miyazaki A Specific Chymase Inhibitor, 2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl]acetamide (NK3201), Suppresses Development of Abdominal Aortic Aneurysm in Hamsters J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 879 - 883. [Abstract] [Full Text] [PDF]
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M. Ishibashi, K.-i. Hiasa, Q. Zhao, S. Inoue, K. Ohtani, S. Kitamoto, M. Tsuchihashi, T. Sugaya, I. F. Charo, S. Kura, et al. Critical Role of Monocyte Chemoattractant Protein-1 Receptor CCR2 on Monocytes in Hypertension-Induced Vascular Inflammation and Remodeling Circ. Res., May 14, 2004; 94(9): 1203 - 1210. [Abstract] [Full Text] [PDF]
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 L. Wu, M. Iwai, Z. Li, T. Shiuchi, L.-J. Min, T.-X. Cui, J.-M. Li, M. Okumura, C. Nahmias, and M. Horiuchi Regulation of Inhibitory Protein-{kappa}B and Monocyte Chemoattractant Protein-1 by Angiotensin II Type 2 Receptor-Activated Src Homology Protein Tyrosine Phosphatase-1 in Fetal Vascular Smooth Muscle Cells Mol. Endocrinol., March 1, 2004; 18(3): 666 - 678. [Abstract] [Full Text] [PDF]
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W. Ni, S. Kitamoto, M. Ishibashi, M. Usui, S. Inoue, K.-i. Hiasa, Q. Zhao, K.-i. Nishida, A. Takeshita, and K. Egashira Monocyte Chemoattractant Protein-1 Is an Essential Inflammatory Mediator in Angiotensin II-Induced Progression of Established Atherosclerosis in Hypercholesterolemic Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 534 - 539. [Abstract] [Full Text]
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A. T Hirsch and D. Duprez The potential role of angiotensin-converting enzyme inhibition in peripheral arterial disease Vascular Medicine, November 1, 2003; 8(4): 273 - 278. [Abstract] [PDF]
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J. M. Proudfoot, K. D. Croft, I. B. Puddey, and L. J. Beilin Angiotensin II Type 1 Receptor Antagonists Inhibit Basal As Well As Low-Density Lipoprotein and Platelet-Activating Factor-Stimulated Human Monocyte Chemoattractant Protein-1 J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 846 - 853. [Abstract] [Full Text] [PDF]
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 R. De Caterina and C. Manes Inflammation in early atherogenesis: impact of ACE inhibition Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A15 - A24. [Abstract] [PDF]
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B. Schieffer Interaction of interleukin-6 and angiotensin II in atherosclerosis: culprit for inflammation? Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A25 - A30. [Abstract] [PDF]
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M. A. Hernandez-Presa, M. Ortego, J. Tunon, J. L. Martin-Ventura, S. Mas, L. M. Blanco-Colio, C. Aparicio, L. Ortega, J. Gomez-Gerique, F. Vivanco, et al. Simvastatin reduces NF-{kappa}B activity in peripheral mononuclear and in plaque cells of rabbit atheroma more markedly than lipid lowering diet Cardiovasc Res, January 1, 2003; 57(1): 168 - 177. [Abstract] [Full Text] [PDF]
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A. Alvarez, C. Hermenegildo, A. C. Issekutz, J. V. Esplugues, and M.-J. Sanz Estrogens Inhibit Angiotensin II-Induced Leukocyte-Endothelial Cell Interactions In Vivo via Rapid Endothelial Nitric Oxide Synthase and Cyclooxygenase Activation Circ. Res., December 13, 2002; 91(12): 1142 - 1150. [Abstract] [Full Text] [PDF]
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D. L. Mann Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future Circ. Res., November 29, 2002; 91(11): 988 - 998. [Abstract] [Full Text] [PDF]
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C. Kluft, R. Kleemann, and M.P.M. de Maat How best to counteract the enemies? By controlling inflammation in the coronary circulation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G53 - G65. [Abstract] [PDF]
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Y. Suzuki, C. Gomez-Guerrero, I. Shirato, O. Lopez-Franco, P. Hernandez-Vargas, G. Sanjuan, M. Ruiz-Ortega, T. Sugaya, K. Okumura, Y. Tomino, et al. Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway J. Immunol., October 15, 2002; 169(8): 4136 - 4146. [Abstract] [Full Text] [PDF]
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 O. Sekine, Y. Nishio, K. Egawa, T. Nakamura, H. Maegawa, and A. Kashiwagi Insulin Activates CCAAT/Enhancer Binding Proteins and Proinflammatory Gene Expression through the Phosphatidylinositol 3-Kinase Pathway in Vascular Smooth Muscle Cells J. Biol. Chem., September 20, 2002; 277(39): 36631 - 36639. [Abstract] [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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A. R. Brasier, A. Recinos III, and M. S. Eledrisi Vascular Inflammation and the Renin-Angiotensin System Arterioscler. Thromb. Vasc. Biol., August 1, 2002; 22(8): 1257 - 1266. [Abstract] [Full Text] [PDF]
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R. Nakamura, K. Egashira, Y. Machida, S. Hayashidani, M. Takeya, H. Utsumi, H. Tsutsui, and A. Takeshita Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure: Roles of Oxidative Stress and Inflammation Circulation, July 16, 2002; 106(3): 362 - 367. [Abstract] [Full Text] [PDF]
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O. Lorenzo, M. Ruiz-Ortega, Y. Suzuki, M. Ruperez, V. Esteban, T. Sugaya, and J. Egido Angiotensin III Activates Nuclear Transcription Factor-{kappa}B in Cultured Mesangial Cells Mainly via AT2 Receptors: Studies with AT1 Receptor-Knockout Mice J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1162 - 1171. [Abstract] [Full Text] [PDF]
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E. Napoleone, A. Di Santo, A. Bastone, G. Peri, A. Mantovani, G. de Gaetano, M. B. Donati, and R. Lorenzet Long Pentraxin PTX3 Upregulates Tissue Factor Expression in Human Endothelial Cells: A Novel Link Between Vascular Inflammation and Clotting Activation Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 782 - 787. [Abstract] [Full Text] [PDF]
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
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D J Brull, J Sanders, A Rumley, G D Lowe, S E Humphries, and H E Montgomery Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release Heart, March 1, 2002; 87(3): 252 - 255. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, V. Esteban, Y. Suzuki, S. Mezzano, J.J. Plaza, and J. Egido Role of the Renin-Angiotensin System in Vascular Diseases: Expanding the Field Hypertension, December 1, 2001; 38(6): 1382 - 1387. [Abstract] [Full Text] [PDF]
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J. Niebauer, P. S Tsao, P. S Lin, R. E Pratt, and J. P Cooke Cholesterol-induced upregulation of angiotensin II and its effects on monocyte-endothelial interaction and superoxide production Vascular Medicine, August 1, 2001; 6(3): 133 - 138. [Abstract] [PDF]
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P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF]
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Y. Funakoshi, T. Ichiki, H. Shimokawa, K. Egashira, K. Takeda, K. Kaibuchi, M. Takeya, T. Yoshimura, and A. Takeshita Rho-Kinase Mediates Angiotensin II-Induced Monocyte Chemoattractant Protein-1 Expression in Rat Vascular Smooth Muscle Cells Hypertension, July 1, 2001; 38(1): 100 - 104. [Abstract] [Full Text] [PDF]
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 A. J. P. Lewington, M. Arici, K. P. G. Harris, N. J. Brunskill, and J. Walls Modulation of the renin-angiotensin system in proteinuric renal disease: are there added benefits? Nephrol. Dial. Transplant., May 1, 2001; 16(5): 885 - 888. [Full Text] [PDF]
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M. Katoh, K. Egashira, C. Kataoka, M. Usui, M. Koyanagi, S. Kitamoto, Y. Ohmachi, A. Takeshita, and H. Narita Regression by ACE inhibition of arteriosclerotic changes induced by chronic blockade of NO synthesis in rats Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2306 - H2312. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, J. Blanco, and J. Egido Systemic Infusion of Angiotensin II into Normal Rats Activates Nuclear Factor-{{kappa}}B and AP-1 in the Kidney : Role of AT1 and AT2 Receptors Am. J. Pathol., May 1, 2001; 158(5): 1743 - 1756. [Abstract] [Full Text] [PDF]
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G. G. Bishop, J. A. McPherson, J. M. Sanders, S. E. Hesselbacher, M. J. Feldman, C. A. McNamara, L. W. Gimple, E. R. Powers, S. A. Mousa, and I. J. Sarembock Selective {{alpha}}v{beta}3-Receptor Blockade Reduces Macrophage Infiltration and Restenosis After Balloon Angioplasty in the Atherosclerotic Rabbit Circulation, April 10, 2001; 103(14): 1906 - 1911. [Abstract] [Full Text] [PDF]
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V. J. Dzau Tissue Angiotensin and Pathobiology of Vascular Disease : A Unifying Hypothesis Hypertension, April 1, 2001; 37(4): 1047 - 1052. [Abstract] [Full Text] [PDF]
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D. Gomez-Garre, R. Largo, N. Tejera, J. Fortes, F. Manzarbeitia, and J. Egido Activation of NF-{{kappa}}B in Tubular Epithelial Cells of Rats With Intense Proteinuria : Role of Angiotensin II and Endothelin-1 Hypertension, April 1, 2001; 37(4): 1171 - 1178. [Abstract] [Full Text] [PDF]
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M. SATOH, N. KASHIHARA, Y. YAMASAKI, K. MARUYAMA, K. OKAMOTO, Y. MAESHIMA, H. SUGIYAMA, T. SUGAYA, K. MURAKAMI, and H. MAKINO Renal Interstitial Fibrosis Is Reduced in Angiotensin II Type 1a Receptor-Deficient Mice J. Am. Soc. Nephrol., February 1, 2001; 12(2): 317 - 325. [Abstract] [Full Text]
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U. Kintscher, S. Wakino, S. Kim, E. Fleck, W. A. Hsueh, and R. E. Law Angiotensin II Induces Migration and Pyk2/Paxillin Phosphorylation of Human Monocytes Hypertension, February 1, 2001; 37(2): 587 - 593. [Abstract] [Full Text] [PDF]
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F. C. Luft Workshop: Mechanisms and Cardiovascular Damage in Hypertension Hypertension, February 1, 2001; 37(2): 594 - 598. [Abstract] [Full Text] [PDF]
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S. Raiden, Y. Pereyra, V. Nahmod, C. Alvarez, L. Castello, M. Giordano, and J. Geffner Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits neutrophil recruitment in the lung triggered by fMLP J. Leukoc. Biol., November 1, 2000; 68(5): 700 - 706. [Abstract] [Full Text]
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L. Piqueras, P. Kubes, A. Alvarez, E. O'Connor, A. C. Issekutz, J. V. Esplugues, and M.-J. Sanz Angiotensin II Induces Leukocyte-Endothelial Cell Interactions In Vivo Via AT1 and AT2 Receptor-Mediated P-Selectin Upregulation Circulation, October 24, 2000; 102(17): 2118 - 2123. [Abstract] [Full Text] [PDF]
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D. Li, T. Saldeen, F. Romeo, and J. L. Mehta Oxidized LDL Upregulates Angiotensin II Type 1 Receptor Expression in Cultured Human Coronary Artery Endothelial Cells : The Potential Role of Transcription Factor NF-{kappa}B Circulation, October 17, 2000; 102(16): 1970 - 1976. [Abstract] [Full Text] [PDF]
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E. Bush, N. Maeda, W. A. Kuziel, T. C. Dawson, J. N. Wilcox, H. DeLeon, and W. R. Taylor CC Chemokine Receptor 2 Is Required for Macrophage Infiltration and Vascular Hypertrophy in Angiotensin II-Induced Hypertension Hypertension, September 1, 2000; 36(3): 360 - 363. [Abstract] [Full Text] [PDF]
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L. M. Blanco-Colio, M. Valderrama, L. A. Alvarez-Sala, C. Bustos, M. Ortego, M. A. Hernandez-Presa, P. Cancelas, J. Gomez-Gerique, J. Millan, and J. Egido Red Wine Intake Prevents Nuclear Factor-{kappa}B Activation in Peripheral Blood Mononuclear Cells of Healthy Volunteers During Postprandial Lipemia Circulation, August 29, 2000; 102(9): 1020 - 1026. [Abstract] [Full Text] [PDF]
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S. Kitamoto, K. Egashira, C. Kataoka, M. Koyanagi, M. Katoh, H. Shimokawa, R. Morishita, Y. Kaneda, K. Sueishi, and A. Takeshita Increased Activity of Nuclear Factor-{kappa}B Participates in Cardiovascular Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis in Rats Circulation, August 15, 2000; 102(7): 806 - 812. [Abstract] [Full Text] [PDF]
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W. Gonzalez, V. Fontaine, M. E. Pueyo, N. Laquay, D. Messika-Zeitoun, M. Philippe, J.-F. Arnal, M.-P. Jacob, and J.-B. Michel Molecular Plasticity of Vascular Wall During NG-Nitro-L-Arginine Methyl Ester-Induced Hypertension : Modulation of Proinflammatory Signals Hypertension, July 1, 2000; 36(1): 103 - 109. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, S. Konig, B. Wittig, and J. Egido Angiotensin II Activates Nuclear Transcription Factor {kappa}B Through AT1 and AT2 in Vascular Smooth Muscle Cells : Molecular Mechanisms Circ. Res., June 23, 2000; 86(12): 1266 - 1272. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, and J. Egido ACE inhibitors and AT1 receptor antagonists--beyond the haemodynamic effect Nephrol. Dial. Transplant., May 1, 2000; 15(5): 561 - 565. [Full Text] [PDF]
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M. Klouche, S. Rose-John, W. Schmiedt, and S. Bhakdi Enzymatically Degraded, Nonoxidized LDL Induces Human Vascular Smooth Muscle Cell Activation, Foam Cell Transformation, and Proliferation Circulation, April 18, 2000; 101(15): 1799 - 1805. [Abstract] [Full Text] [PDF]
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D. Li and J. L. Mehta Upregulation of Endothelial Receptor for Oxidized LDL (LOX-1) by Oxidized LDL and Implications in Apoptosis of Human Coronary Artery Endothelial Cells : Evidence From Use of Antisense LOX-1 mRNA and Chemical Inhibitors Arterioscler. Thromb. Vasc. Biol., April 1, 2000; 20(4): 1116 - 1122. [Abstract] [Full Text] [PDF]
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B. Schieffer, E. Schieffer, D. Hilfiker-Kleiner, A. Hilfiker, P. T. Kovanen, M. Kaartinen, J. Nussberger, W. Harringer, and H. Drexler Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques : Potential Implications for Inflammation and Plaque Instability Circulation, March 28, 2000; 101(12): 1372 - 1378. [Abstract] [Full Text] [PDF]
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W. B Strawn, R. H Dean, and C. M Ferrario Novel mechanisms linking angiotensin II and early atherogenesis Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 11 - 17. [PDF]
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E. Napoleone, A. Di Santo, M. Camera, E. Tremoli, and R. Lorenzet Angiotensin-Converting Enzyme Inhibitors Downregulate Tissue Factor Synthesis in Monocytes Circ. Res., February 4, 2000; 86(2): 139 - 143. [Abstract] [Full Text] [PDF]
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M. Usui, K. Egashira, H. Tomita, M. Koyanagi, M. Katoh, H. Shimokawa, M. Takeya, T. Yoshimura, K. Matsushima, and A. Takeshita Important Role of Local Angiotensin II Activity Mediated via Type 1 Receptor in the Pathogenesis of Cardiovascular Inflammatory Changes Induced by Chronic Blockade of Nitric Oxide Synthesis in Rats Circulation, January 25, 2000; 101(3): 305 - 310. [Abstract] [Full Text] [PDF]
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C. E. Donovan, D. A. Mark, H. Z. He, H.-C. Liou, L. Kobzik, Y. Wang, G. T. De Sanctis, D. L. Perkins, and P. W. Finn NF-{kappa}B/Rel Transcription Factors: c-Rel Promotes Airway Hyperresponsiveness and Allergic Pulmonary Inflammation J. Immunol., December 15, 1999; 163(12): 6827 - 6833. [Abstract] [Full Text] [PDF]
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H. Soejima, H. Ogawa, H. Yasue, K. Kaikita, K. Takazoe, K. Nishiyama, K. Misumi, S. Miyamoto, M. Yoshimura, K. Kugiyama, et al. Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction J. Am. Coll. Cardiol., October 1, 1999; 34(4): 983 - 988. [Abstract] [Full Text] [PDF]
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R. Kranzhofer, J. Schmidt, C. A. H. Pfeiffer, S. Hagl, P. Libby, and W. Kubler Angiotensin Induces Inflammatory Activation of Human Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., July 1, 1999; 19(7): 1623 - 1629. [Abstract] [Full Text] [PDF]
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A. Nicoletti and J.-B. Michel Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors Cardiovasc Res, March 1, 1999; 41(3): 532 - 543. [Abstract] [Full Text] [PDF]
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R. Largo, D. Gomez-Garre, K. Soto, B. Marron, J. Blanco, R. M. Gazapo, J. J. Plaza, and J. Egido Angiotensin-Converting Enzyme Is Upregulated in the Proximal Tubules of Rats With Intense Proteinuria Hypertension, February 1, 1999; 33(2): 732 - 739. [Abstract] [Full Text] [PDF]
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F. C. Luft, E. Mervaala, D. N. Muller, V. Gross, F. Schmidt, J. K. Park, C. Schmitz, A. Lippoldt, V. Breu, R. Dechend, et al. Hypertension-Induced End-Organ Damage : A New Transgenic Approach to an Old Problem Hypertension, January 1, 1999; 33(1): 212 - 218. [Abstract] [Full Text] [PDF]
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C. Bustos, M. A. Hernandez-Presa, M.o. Ortego, J. Tunon, L. Ortega, F. Perez, C. Diaz, G. Hernandez, and J. Egido HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis J. Am. Coll. Cardiol., December 1, 1998; 32(7): 2057 - 2064. [Abstract] [Full Text] [PDF]
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M. A. Hernandez-Presa, C. Bustos, M. Ortego, J. Tunon, L. Ortega, and J. Egido ACE Inhibitor Quinapril Reduces the Arterial Expression of NF-{kappa}B-Dependent Proinflammatory Factors but not of Collagen I in a Rabbit Model of Atherosclerosis Am. J. Pathol., December 1, 1998; 153(6): 1825 - 1837. [Abstract] [Full Text] [PDF]
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M. E. Ritchie Nuclear Factor-{kappa}B Is Selectively and Markedly Activated in Humans With Unstable Angina Pectoris Circulation, October 27, 1998; 98(17): 1707 - 1713. [Abstract] [Full Text] [PDF]
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M. Katoh, K. Egashira, M. Usui, T. Ichiki, H. Tomita, H. Shimokawa, H. Rakugi, and A. Takeshita Cardiac Angiotensin II Receptors Are Upregulated by Long-Term Inhibition of Nitric Oxide Synthesis in Rats Circ. Res., October 5, 1998; 83(7): 743 - 751. [Abstract] [Full Text] [PDF]
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M. Klouche, S. Gottschling, V. Gerl, W. Hell, M. Husmann, B. Dorweiler, M. Messner, and S. Bhakdi Atherogenic Properties of Enzymatically Degraded LDL : Selective Induction of MCP-1 and Cytotoxic Effects on Human Macrophages Arterioscler. Thromb. Vasc. Biol., September 1, 1998; 18(9): 1376 - 1385. [Abstract] [Full Text] [PDF]
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