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B and AP-1 and
upregulation of ICAM-1 in reperfused canine heart
Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated whether oxygen
radicals generated during ischemia-reperfusion trigger
postischemic inflammation in the heart. Closed-chest dogs
underwent 90-min coronary artery occlusion, followed by 1- or 3-h
reperfusion: 10 dogs received the cell-permeant oxygen radical
scavenger N-(2-mercaptopropionyl)-glycine (MPG; 8 mg · kg
1 · h1
intracoronary) beginning 5 min before reperfusion, and 9 dogs received
vehicle. Blood flow (microspheres), intercellular adhesion molecule
(ICAM)-1 protein expression (immunohistochemistry), ICAM-1 gene activation (Northern blotting), nuclear DNA binding activity of nuclear factor (NF)-
B and AP-1 (electrophoretic
mobility shift assays), and neutrophil (PMN) accumulation
(myeloperoxidase activity) were assessed in myocardial tissue samples.
ICAM-1 protein expression was high in vascular endothelium after
ischemia-reperfusion but was markedly reduced by MPG. MPG
treatment also markedly decreased expression of ICAM-1 mRNA and tissue
PMN accumulation. Nuclear DNA binding activities of NF-B and AP-1,
increased by ischemia-reperfusion, were both markedly decreased
by MPG at 1 h of reperfusion. However, by 3 h, AP-1 activity
was only modestly reduced by MPG and NF-B activity was not
significantly different from ischemic-reperfused controls.
These results suggest that oxygen radicals generated in vivo during
reperfusion trigger early activation of NF-B and AP-1,
resulting in upregulation of the ICAM-1 gene in vascular endothelium
and subsequent tissue accumulation of activated PMNs.
reperfusion injury; oxidative stress; neutrophils; vascular endothelium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RESTORATION OF BLOOD FLOW to ischemic tissue may result in acute inflammation and an extension of ischemia-related tissue damage. The genesis of postischemic inflammation is complex and involves activation of vascular endothelium, genetic upregulation of endothelial cell adhesion proteins and proinflammatory cytokines, and infiltration of neutrophils (PMNs). Intercellular adhesion molecule (ICAM)-1 is thought to play a central role in the trapping and accumulation of activated PMNs in ischemic-reperfused myocardium (21). Monoclonal antibodies directed against ICAM-1 or its ligand on PMNs (the integrins CD11a/CD18 and CD11b/CD18) reduce cardiac microvascular and parenchymal cell injury in animal models (14, 27, 48). In addition, mutant mice deficient in ICAM-1 are less susceptible to cerebral (43) and renal (19) damage after transient ischemia-reperfusion.
On the basis of in vitro models, the ICAM-1 gene is thought to be
regulated by the nuclear transcription factor nuclear factor (NF)-B,
which is normally complexed to the cytoplasmic inhibitory protein
IB. Through a cascade of kinase enzymes, including protein kinase C
(38), tyrosine kinases (36), and IB
kinases (9) and involving the intracellular generation of
reactive oxygen species (ROS) (22), IB is
phosphorylated, ubiquitinated, and degraded by proteasomes, which
release NF-B from IB and allow it to translocate to the nucleus.
Inhibition of NF-B by diverse means has been shown to block ICAM-1
induction in vitro (26, 35, 38, 46) and in intact hearts
(23).
The importance of ROS in these processes is unclear. In vitro,
antioxidants can block NF-B activation in many but not all cell
types (3, 22). In addition, the involvement of ROS appears to be strongly stimulus dependent (3). ROS, by changing
cellular redox state, may induce or enhance NF-B activation by
modifying the activity of one or more of the kinase enzymes in the
NF-B activation cascade (22). However, ROS could also
directly regulate gene transcription independent of NF-B and could
enhance transcription by activating other redox-sensitive transcription
factors, including AP-1 (41). A distinct
H2O2-responsive element has been localized in
the ICAM-1 promoter, separate from the NF-B binding site, containing
binding sites for AP-1 and Ets (39).
This study was done to determine whether ROS generated at the time of
coronary reperfusion play an important role in vivo in the activation
of transcription factors NF-B and AP-1, the expression of ICAM-1,
and the initiation of acute inflammation in postischemic myocardium.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Healthy adult mongrel dogs were anesthetized with thiopental sodium (25 mg/kg iv), intubated, and ventilated with 0-2% halothane, with the concentration adjusted to maintain a stable arterial pressure. Through small skin incisions, 8-Fr sheaths were placed in both femoral arteries. A 6-Fr pigtail catheter was passed through the left sheath into the left ventricle for injection of microspheres to measure blood flow. The sidearm was used for blood pressure monitoring and microsphere sampling. A 7-Fr guiding catheter was introduced through the right sheath and advanced to the aortic root.
After stabilization, an angioplasty catheter (balloon 10 mm in length and 2.5-3.5 mm in diameter) was inserted through the guiding catheter into the proximal left anterior descending coronary artery (LAD). Myocardial ischemia was induced by inflating the balloon to 3-5 atm to occlude the LAD. After 90 min, the balloon was completely deflated and the myocardium was reperfused. Additional dogs (n = 5) had all of the instrumentation described above but without balloon inflation (sham occlusion). Coronary angiography was performed before and shortly after coronary occlusion, just before balloon deflation, and at the end of reperfusion to confirm that complete arterial occlusion and reperfusion were achieved.
Dogs were randomly assigned to two groups. In the first group (I/R-MPG;
n = 7), intracoronary infusion of
N-(2-mercaptopropionyl)-glycine (MPG, 8 mg · kg1 · h1; Sigma) began
5 min before reperfusion and ended just before death 3 h later.
The infusion was administered through the central lumen of the balloon
catheter into the distal coronary artery with a volumetric infusion
pump (IMED, San Diego, CA). MPG was dissolved in a mixture of 77%
heparinized normal saline and 23% water (isosmotic with plasma) to a
concentration of 10 mg/ml. In the second group (I/R; n = 6), dogs received an equivalent volume of vehicle for 3 h,
beginning 5 min before reperfusion. An identical protocol was carried
out in another series of dogs, except that reperfusion and
intracoronary infusion of MPG or vehicle was carried out for only
1 h (n = 3 each for MPG and vehicle). These latter
animals were used for assessment of NF-B and AP-1 activation based
on our finding that activation of these transcription factors peaks at
1 h of reperfusion in this model.
At the end of the reperfusion period, hearts were arrested by rapid
intravenous infusion of potassium chloride and removed from the chest
and the left ventricle was opened flat. Tissue specimens (4 g) were
quickly excised from the center and the border of the
ischemic-reperfused myocardium as well as from the
nonischemic region of the left ventricle. A consistent sampling
protocol was used to obtain five transmural samples from the
ischemic anterior wall and two from the nonischemic
posterior wall. Samples were crudely defined as being "central" or
"border" within the ischemic region based on the gross
anatomic distribution of the LAD. Each sample was divided into three
full-thickness pieces, which were then further divided into inner
(endocardial) and outer (epicardial) halves. The central portion of
each sample was used for microsphere blood flow determination; a second
portion was processed for immunohistochemical staining of ICAM-1
protein; the third was fast frozen in liquid nitrogen and stored at
80°C for ICAM-1 mRNA analysis, assessment of NF-B or AP-1 DNA
binding activity, or measurement of myeloperoxidase (MPO) activity (an
index of PMN accumulation). In dogs reperfused for 1 h, the frozen
samples were used only for assessment of NF-B or AP-1. In each
heart, at least four samples were analyzed for ICAM-1 protein, ICAM-1
mRNA, and NF-B and AP-1 DNA binding and three samples were analyzed
for MPO activity. The need for rapid freezing of myocardial samples
precluded measurements of myocardial infarct size.
Regional myocardial blood flow measurement. Regional myocardial blood flow was determined with radioactive (DuPont, North Billerica, MA) or fluorescent nonradioactive (NuFLOW; Interactive Medical Technology, Los Angeles, CA) microspheres at baseline, 80 min after occlusion, 10 min after reperfusion, and 10 min before death with standard techniques (4, 15).
Immunohistochemistry.
The location and extent of ICAM-1 protein expression were assessed by
immunohistochemistry. Fresh myocardial samples were imbedded in optimum
cutting temperature compound, immediately frozen in isopentane
precooled with dry ice, and stored at 80°. Cryostat
sections were cut 5 µm thick and fixed in alumina-filtered acetone.
Staining was performed with the avidin-biotin immunoperoxidase technique. Sections were incubated for 60 min with primary antibody (CL18/6) and subsequently for 30 min with biotinylated secondary antibody (Jackson Immunoresearch Laboratories, West Grove, PA). CL18/6
is an anti-canine ICAM-1 IgG1 antibody developed as previously described (42). Negative controls included omission of the
primary and/or secondary antibodies.
RNA preparation and Northern blot analysis.
Myocardial samples stored at 80°C were homogenized with a Polytron
tissue homogenizer. Total RNA was isolated by a modification of
the guanidinium-phenol-chloroform extraction method.
Approximately 20 µg of total RNA per lane was fractionated by
1% agarose-formaldehyde gel electrophoresis and transferred to a nylon
membrane (Gene-Screen Plus, NEN DuPont, Boston, MA). RNA was fixed by
cross-linking in a UV Stratalinker-1800 (Stratagene, La Jolla, CA).
After being prehybridized for 3 h at 65°C in a mixture of 0.5 M
phosphate buffer, 1% BSA, 1% SDS, and 10 mM EDTA, the blots were
hybridized overnight under the same stringent conditions with a
previously described cDNA probe for canine ICAM-1 mRNA
(42). The probe was radiolabeled with
[
-32P]dCTP to a specific activity of >1 × 106 cpm by random priming. Blots were washed, exposed to
Kodak X-ray films with intensifying screens for an appropriate time at
80°C, and analyzed by densitometry (Imagequant, Molecular Dynamics, Sunnyvale, CA). To control for variability in the loaded quantity of
total RNA, all filters were probed with a 24-bp oligonucleotide probe
(5'-ACGGTATCTGATCGTCTTCGAACC) corresponding to 18S rRNA that was
end-labeled with a terminal deoxynucleotidyl transferase (Amersham Life
Science, Arlington Heights, IL). The 18S rRNA band was used to
normalize mRNA for ICAM-1. Positive-control myocardium was obtained
from a pentobarbital sodium-anesthetized dog injected with
lipopolysaccharide (LPS; 1 mg/kg iv). The animal was killed 5 h
later with an overdose of anesthetic, and the heart was removed and
samples were excised from the left ventricular free wall, snap-frozen,
and processed as described above.
Preparation of nuclear extracts.
Myocardial samples were homogenized at 4°C in hypotonic buffer,
filtered, allowed to swell in a cold room for 15 min, and centrifuged
at 850 g for 15 min at 4°C. After the supernatants were
discarded, the nuclear pellets were washed and proteins were recovered
by centrifugation (30 min at 20,000 g). The protein concentration of the supernatant was determined with Coomassie blue.
Nuclear extracts were stored at 80°C.
Electrophoretic mobility shift assay.
Double-stranded oligonucleotides containing consensus-binding sequences
for NF-B (Promega) were used to assay for binding activity in the
nuclear extracts. The oligonucleotides were labeled with
[-32P]dATP by fill-in reaction with the Klenow
fragment of DNA polymerase I. Nuclear extracts (5 µg) were mixed with
20,000 cpm of the appropriate 32P-labeled oligonucleotides
in 10 µl of buffer, and the reaction products were separated on a 4%
nondenaturing polyacrylamide gel. Gels were then dried and exposed to
X-ray film at 80°C.
MPO activity. Frozen myocardial samples from the ischemic and normal regions were homogenized under liquid nitrogen. MPO was released by freeze-thawing and assayed with H2O2 and o-dianisidine as previously described (34).
Statistical analysis.
All values are given as means ± SE. Hemodynamic parameters and
regional myocardial blood flow during ischemia and reperfusion in each group were compared by repeated-measures analysis of variance. Comparisons of ICAM-1 mRNA and protein expression and of nuclear DNA
binding of NF-B and AP-1 among the two groups and the sham dogs were
done by analysis of variance with Duncan's test for multiple
comparisons. MPO activities were compared by Student's t-test.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Hemodynamics and myocardial blood flow.
Of the 19 dogs randomized, 3 were excluded because of technical
problems (1 with repeated episodes of ventricular fibrillation, 2 with
failure of adequate coronary occlusion). In the remaining animals,
there were no significant changes in systolic or diastolic arterial
blood pressure or heart rate during coronary occlusion or 3-h
reperfusion and no significant differences in these variables at any
time point between the I/R and I/R-MPG groups. Similarly, there were no
significant differences between the two groups in blood flow to the
center or border of the ischemic zone, or to the
nonischemic region, at any time point. During coronary
occlusion, all dogs demonstrated severe ischemia in the central
endocardial portion of the ischemic region (flow 
0.07 ml · min1 · g1).
Immunohistochemistry of ICAM-1 protein.
A high level of ICAM-1 protein expression was seen on the endothelium
of venules, arterioles, and capillaries in samples from myocardium
reperfused for 180 min in the I/R group (Fig.
1A). ICAM-1 expression was
markedly reduced at 180 min of reperfusion in dogs given intracoronary
MPG shortly before reperfusion (Fig. 1B), to levels similar
to those observed in sham-occluded control animals. As shown by a
semiquantitative scoring system (30) and blinded reading
of tissue samples, MPG resulted in highly significant decreases in
endothelial ICAM-1 staining in arterioles, venules, and capillaries
(P < 0.002 for each; Fig.
2). No myocyte staining was observed in
any of the experimental groups.
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ICAM-1 mRNA expression.
ICAM-1 mRNA was present at 180 min of reperfusion in myocardium from
the ischemic region in I/R dogs but was undetectable in
sham-occluded dogs (Fig. 3). Expression
of ICAM-1 mRNA at 180 min of reperfusion was stronger in center
compared with border samples. MPG treatment resulted in a decrease in
ICAM-1 mRNA expression in both areas (Fig. 3). Quantitation of ICAM-1
bands demonstrated a 32% reduction in expression in central samples
and a 41% reduction in border samples in the MPG group
(P < 0.08 for central samples, P < 0.02 for border samples, and P < 0.003 for all samples
combined; Fig. 4).
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Activation of nuclear transcription factors.
Both NF-B and AP-1 binding activities were high compared with those
of sham-occluded controls in nuclear extracts from myocardium reperfused for 1 or 3 h in the I/R group (Figs.
5 and 6).
Supershift assays demonstrated that NF-B complexes
contained p65 and p50 subunits but not p52 or c-Rel (Fig.
5C), whereas AP-1 contained mainly c-Fos and, to a lesser
extent, c-Jun (Fig. 6C). Quantitation of bands by
densitometry revealed that MPG produced a marked reduction in DNA
binding activity for both transcription factors at 1 h of
reperfusion (NF-B, 88% vs. 15% of LPS-positive control; AP-1, 86%
vs. 22% of LPS-positive control; both P < 0.001) to
levels not significantly different from those in sham-occluded dogs
(Fig. 7). At 3 h of reperfusion, the
MPG treatment effect was much less pronounced. AP-1 binding activity in
the MPG group was mildly reduced compared with that in the I/R group
(117% vs. 84% of LPS-positive control; P < 0.05),
but NF-B binding activity was not reduced (52% vs. 44% of
LPS-positive control). Both AP-1 and NF-B binding activities in the
MPG group were significantly greater at 3 h than in sham-occluded
dogs (Fig. 7).
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MPO activity.
Tissue MPO activity was increased five- to sevenfold in endocardial and
epicardial samples from the center of the ischemic region in
control dogs reperfused for 180 min (Fig.
8). MPG treatment resulted in an ~70%
decrease in MPO activity in pooled endocardial and epicardial samples
from the ischemic region (0.028 ± 0.007 vs. 0.100 ± 0.019 IU/100 mg; P < 0.003). Activity in
nonischemic myocardium was low in both groups and not
significantly different.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our study showed that administration of MPG, a cell-permeant
oxygen radical scavenger, beginning shortly before reperfusion resulted
in less activation of the redox-sensitive nuclear transcription factors
NF-B and AP-1, reduced expression of ICAM-1 at both mRNA and protein
levels, and decreased PMN accumulation in the reperfused myocardium.
These results suggest that ROS generated at reperfusion are
responsible, at least in part, for initiation of postischemic inflammation in vivo through upregulation of ICAM-1 and possibly other
important proinflammatory genes.
Role of ROS in activation of NF-B and AP-1.
Our findings are consistent with the hypothesis that oxidant stress
leads to activation and nuclear translocation of NF-B and AP-1 and
that these factors, in turn, promote ICAM-1 gene transcription through
interaction with specific binding sites in the promoter region.
Separate binding sites have been identified for NF-B and AP-1
(24, 39), but it is not exactly clear how transcription of
ICAM-1 is regulated or how ROS are involved in the process. ROS could
function merely to regulate the level of transcription factors, but
they could also act directly by modifying the binding of transcription
factors to DNA or regulating their transcriptional activities after
binding (41). ROS could also affect transcription rates by
increasing the steady-state level or the rate of spontaneous
oscillations of intracellular calcium concentration (10,
18).
B and AP-1 (8, 40).
Hypoxia-reoxygenation or proinflammatory cytokines such as tumor
necrosis factor (TNF)- also induce NF-B activation through
intracellular generation of ROS by a membrane-bound NADPH oxidase
(11, 37). In many studies, addition of antioxidants, such
as N-acetyl-cysteine or pyrrolidinedithiocarbamate
(PDTC), or inhibitors of NADPH oxidase (such as
diphenyleneiodium) block cytokine-induced ROS production, NF-B
activation, and/or adhesion molecule expression in endothelial cells
(11, 12, 29, 41). However, Bowie and O'Neill
(3) argued that much of the in vitro evidence supporting a
central role for ROS in NF-B activation is specific to a particular
stimulus in a particular cell line. They showed that the activation of
NF-B by H2O2 is cell specific and distinct
from physiological activators such as TNF- and interleukin-1, whereas inhibition by antioxidants is also cell- and stimulus specific.
In our study, MPG markedly reduced NF-B and AP-1 activation after
1 h of reperfusion but had only a modest effect on AP-1 and no
effect on NF-B after 3 h. This suggests that ROS may initiate early transcription factor activation but that additional factors, e.g., cytokines, may contribute to persistence of early activation or
new activation over several hours.
Few in vivo studies have addressed the role of ROS in transcription
factor activation and adhesion molecule expression after ischemia-reperfusion. Diethyldithiocarbamate (DDC) was shown to inhibit activation of NF-B and expression of cytokine and inducible nitric oxide synthase genes in myocardium after brief ischemia (5). After LPS challenge in rats, PDTC inhibited NF-B
activation, induction of ICAM-1, and infiltration of PMNs in the heart,
lungs, and liver (25).
Source and species of ROS.
The source and species of ROS responsible for these processes have not
been clearly defined. ROS generated during reperfusion are believed to
derive mainly from endothelial cells as a by-product of the xanthine
oxidase reaction, although a vascular NADPH oxidase containing the
small GTP-binding protein Rac-1 may also contribute (44).
Tissue macrophages and activated PMNs probably represent a significant
external source of ROS during ischemia-reperfusion. Although
O
B and AP-1 activation, MPG is a thiol
compound and may have worked by replenishing reduced sulfhydryl groups
and reducing oxidative stress. In the presence of glutathione
peroxidase, reduced glutathione (GSH) reacts more rapidly with MPG than
peroxides, tending to replenish reduced GSH stores. In vitro,
GSH depletion in human umbilical vein endothelial cells resulted in
increased ICAM-1 expression and PMN adhesion, which could be inhibited
by introduction of decoy oligonucleotide sequences for NF-B or AP-1
(20). GSH inhibited phosphorylation of IB by TNF-
(6), whereas overexpression of -glutamylcysteine synthetase (to raise cellular levels of GSH) blocked NF-B and AP-1
activation induced by TNF- but not by H2O2
(28). MPG has also been shown to inhibit
myoglobin-H2O2-mediated peroxidation reactions,
independent of ·OH formation (33).
MPG was shown previously to inhibit the expression of ICAM-1 and the
increased PMN adhesion induced by anoxia-reoxygenation in cultured rat
aortic endothelial cells (1). In vivo, MPG was shown to
block activation of NF-B in the rabbit heart after ischemia-reperfusion (47). When infused during
reperfusion, MPG reduced myocardial infarct size by ~50% in canine
models (16, 17, 32) but had only equivocal effects in the
rabbit (31). Protection by MPG has been attributed to the
prevention of ROS-induced membrane oxidation, but our results suggest
that inhibition of inflammation-mediated damage might also be
responsible. Effective scavenging of ROS or maintenance of cellular
redox state may represent a useful therapeutic approach for limiting
inflammation-mediated myocardial reperfusion injury.
Limitations.
Our study addressed whether ROS may trigger the early activation of
NF-B and AP-1 after ischemia-reperfusion, leading to rapid
ICAM-1 upregulation. Although MPG markedly inhibited transcription factor activation at 1 h of reperfusion, the effect was
considerably less pronounced at 3 h, suggesting that MPG might
have delayed but not eliminated upregulation of the inflammatory
response. However, we did not measure tissue ROS levels or MPG
concentrations, so it is not known whether ROS were suppressed equally
well or whether tissue MPG levels remained equally high throughout the reperfusion period. The concentration of MPG infused in this study has
been shown to markedly suppress ROS production early after ischemia-reperfusion (2), but its effects on ROS
production over several hours are unknown. Mechanisms independent of
ROS may be responsible for delayed upregulation of proinflammatory proteins.
B and the c-Fos subunit of AP-1 are both localized
primarily in vascular endothelium. On the basis of these data, we
believe that the changes we describe in this study occurred principally in vascular endothelial cells.
This study has not defined the precise mechanism of MPG's effect. As
noted above, MPG is an antioxidant with potent ·OH scavenging properties but is not a specific scavenger for this radical species. MPG could act by replenishing tissue GSH stores or inhibiting peroxidation reactions. In all likelihood, however, its effects in this
study are attributable to its antioxidant properties.
Although antioxidants may prove useful in preventing
inflammation-related ischemia-reperfusion injury, more work is
needed to define which agents are most effective, how long they should be administered, and whether there are any downsides to their use.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant P50-HL-52315 (Specialized Center of Research in Ischemic Heart Disease).
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FOOTNOTES |
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Present address of B. Sun: Professor of Medicine, Cardiology Dept., Shanghai First Peoples Hospital, Shanghai, China, 200080.
Address for reprint requests and other correspondence: L. C. Becker, Johns Hopkins Medical Institutions, 600 N. Wolfe St., Halsted 500, Baltimore, MD 21287 (E-mail: lbecker{at}mail.jhmi.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00796.2000
Received 16 August 2000; accepted in final form 4 January 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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