(Circulation. 1999;99:1492-1498.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Tissue Expression and Immunolocalization of Tumor Necrosis Factor-
in Postinfarction Dysfunctional Myocardium
From The Centre for Cardiovascular Research, The Toronto Hospital (M.W.I., S.M., R.Q., A.Y., F.D., W.H.W., Z.S., P.L.), Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology (J.M.P.), University of Toronto, Canada, and VA Medical Center, Baylor College of Medicine, Houston, Tex (D.L.M.).
Correspondence to Peter Liu, MD, 12 EC-324, The Toronto Hospital, General Division, Toronto, Ontario M5G 2C4, Canada. E-mail peter.liu{at}utoronto.ca
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Abstract |
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Background—Tumor necrosis factor-
(TNF-) is markedly elevated in advanced heart failure. It
is not known whether tissue TNF- is elevated in the common setting
of myocardial infarction leading to heart failure and what the source
of TNF- is. To determine this, we studied the expression and protein
localization of TNF- and its 2 main receptors (TNF-R1/R2) in a rat
model of large infarction.
Methods and Results—Male rats were randomized to proximal left
anterior descending ligation. The animals were killed on days 1, 3, 10,
and 35 after ligation to examine gene expression and protein
production of TNF- and TNF-R1/R2 from the infarct,
peri-infarct, and contralateral zones of infarcted heart. There was
increased TNF- mRNA production throughout the
myocardium at day 1, and detectable expression persisted to
day 35 after myocardial infarction. The expression of this
cytokine is not confined strictly to the infarct or
peri-infarct zones but is expressed by cardiac myocytes within the
myocardium in the contralateral normal zone. Changes in
gene expression are mirrored initially by augmented protein
production within the myocytes. Levels of TNF- protein in
the infarct and peri-infarct zones rose early to 8- to 10-fold above
normal levels and rose to 4- to 5-fold in the contralateral zone.
Finally, expression of the TNF-R1 mRNA transcripts was upregulated at
days 3 and 10 after ligation in the infarct and peri-infarct zones,
suggesting that the signal transduction pathways necessary for TNF-
in the heart remain intact as TNF- biosynthesis increases.
Conclusions—TNF- is present early in a model of large
myocardial infarction and is sustained into the later stage within the
myocardium. Expression of this cytokine is not only
confined strictly to the infarct or peri-infarct zone but is expressed
by cardiac myocytes within the myocardium contralateral to
the infarct. Therefore TNF- production forms a part of an
important intrinsic myocardial stress response system to injury.
Key Words: tissue • myocardium • infarction • heart failure • remodeling • cytokines • tumor necrosis factor
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The adaptive capacity of heart to undergo remodeling after myocardial infarction determines whether the heart will maintain its function at the expense of hypertrophic growth or progress to heart failure. Although the exact biochemical mechanisms responsible for the transition from hemodynamic compensation to decompensation are still unknown, clinical data have shown that circulating level of proinflammatory cytokines, such as tumor necrosis factor-
(TNF-), are elevated after heart
failure.1 2 TNF- is a pleiotropic intercellular
cytokine that is found in almost all cells as part of the
injury response repertoire.3 4 TNF- binds cell surface
receptors TNF-R1 and TNF-R2, which on activation mediate most of the
physiological responses of TNF-, including
negative inotropic effects and apoptosis in cardiac
myocytes.5 6 7 Although the precise biological function for
stress-induced TNF- expression within the heart still is unknown,
the observation that TNF- induces a hypertrophic growth response and
apoptosis in cardiac myocytes suggests that it has an important
role in myocardial homeostasis.
Previous studies have shown that TNF- is upregulated in the
myocardium in response to a variety of forms of cardiac
injury, including transient myocardial ischemia and
reperfusion.8 9 However, it is unclear from existing
studies whether TNF- is also expressed in the myocardium
chronically after injury, such as acute myocardial infarction. Given
the recent observation that TNF- can be produced by a variety of
different cell types in the myocardium in response to
environmental injury10 11 as well as the observation that
TNF- can produce left ventricular (LV)
dysfunction,12 13
cardiomyopathy14 and pulmonary
edema,15 16 it has been suggested that persistent
cytokine overexpression in the myocardium may
contribute to the adverse cardiac remodeling and progressive LV
dysfunction that occurs after acute myocardial infarction. Accordingly,
to determine whether TNF- is expressed in the myocardium
in a chronic model of cardiac injury, we examined both the temporal and
spatial expressions of TNF- as well as TNF receptors within the
myocardium in a rat chronic model of infarction by
coronary artery ligation.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Creation of Rat Myocardial Infarction Model
A rat model of large myocardial infarction leading to LV dysfunction was used for this study, as previously described by our laboratory.17 Male Sprague-Dawley rats 12 to 14 weeks old (n=54) were randomized to proximal left anterior descending (LAD) ligation (n=44) or sham-operated groups (n=10). This ligation creates a reproducible large lateral wall infarction. To further ensure uniformity of infarct, only hearts (n=20) with infarct of
40% of
midwall circumference, which were identified and measured by
pathological and morphometric methods, were included in the final
analysis. The animals were randomized to be killed on days 1,
3, 10, and 35 after coronary ligation, with 5 rats at each of
the time points. The heart was removed aseptically and then divided
transversely at the level of the papillary muscle. The distal portion
was collected for in situ hybridization and immunohistochemical
staining studies. A midpapillary slice was taken from the remaining
proximal portion of the specimen and divided into blocks
representing the midinfarct zone, the peri-infarct zone,
and the contralateral noninfarct zone for Northern blot and ELISA
analysis. The rats with sham-operated hearts were also killed
at the same time points as the ligated group, and heart slices were
obtained at the identical level of papillary muscle as were the ligated
hearts.
Determination of Gene Expression by Northern Blot Analysis
RNA was isolated from frozen tissue samples that were
homogenized and then extracted by the acid guanidinium
thiocyanate-phenol-chloroform method, as described by Chomczynski and
Sacchi.18 Levels of gene expression were detected by
Northern blot analysis. In brief, total RNA (20 µg) was
denatured in formaldehyde, run in 1.2% agarose-formaldehyde gel, and
transferred overnight onto positively charged nylon membrane (Nytran,
Schleicher & Schuell Inc). After prehybridization for 4 hours at
42°C, filters were hybridized overnight at 42°C in fresh
prehybridization buffer [4xSSC, 40% formamide, 1xDenhardt's
solution, 1% SDS, 100 g/mL denatured salmon sperm DNA (Pharmacia)]
containing the denatured 32P-labeled specific
cDNA probes. The filter was sequentially washed for 30 minutes twice
with 1xSSC at 55°C, followed by washing in 0.2xSSC and 0.2% SDS at
60°C until the radioactive background was negligible. TNF-
expression was quantitated by scanning densitometry and normalized to
the expression of GAPDH.17
A full-length mouse TNF- cDNA probe in pGEM was a gift from Dr John
C. Marshall (Toronto, Ontario). A short-length mouse TNF-
cDNA probe of 
700 bp between 375 and 1065 of the coding region was
generated by polymerase chain reaction (PCR) and inserted into a TA
vector (Invitrogen). The mouse TNF-R1 probe was generated in Dr
J. Penninger's laboratory by RT-PCR of the 3'-end of TNF-R1 mRNA, and
the cDNA was inserted into a pBluescript vector. The TNF-R2 probe was
generated by reverse transcription (RT) of total mouse cellular RNA
followed by the PCR to generate a specific cDNA fragment. The first
cDNA strand was carried out with the use of oligo(dt) (a cDNA synthesis
kit from Life Technologies, Gaithersburg, Md).
Oligonucleotide primers used to amplify a 676-bp cDNA
fragment of TNF-R2 from 780 to 1456 of the coding region are
5'-GCTTCCAATTGGTCTGATTG-3' and 5'-ATCCCTTTGCAGGGTGTTAC-3'. All of the
cDNA constructs were confirmed by DNA sequence analysis.
Localization of Gene Expression by In Situ Hybridization
Riboprobes for in situ hybridization were generated from
linearized templates with T7 or SP6 polymerase. TNF- riboprobes were
generated from a 700-kb cloned TNF- cDNA in TA vector as described
above. Antisense TNF- riboprobe was synthesized with SP6 RNA
polymerase on the EcoRI linearized clone. Sense probe was
synthesized by T7 RNA polymerase on the PstI linearized
clone. The probes were labeled with a commercially available RNA color
kit (Amersham Life Science) according to the manufacturer's
specifications.
The tissue sections were hybridized with specific riboprobe in a humidified chamber for 8 hours at 55°C. After washing in TBS (100 mmol/L Tris-HCl, pH 7.5, 400 mmol/L NaCl, 50 mmol/L MgCl2) for 5 minutes with shaking, sections were blocked in 20% NGS and Amersham's blocking agent in TBS at RT for 1 hour. The slides were then incubated for 1 hour with anti–fluorescein alkaline phosphatase conjugate. After the enzymatic reaction, slides were left to develop in the dark for 20 hours at 4°C. The slides were counterstained with 1% neutral red.
Determination of Tissue and Serum TNF- Content by ELISA
Assay
The myocardial homogenate was suspended in PBS
solution containing protease inhibitors (PMSF 14.9
mmol/L, leupeptin 21 nmol/L, aprotinin 3.1 nmol/L). After
centrifugation for 20 minutes at 20 000g,
the supernatant, which contained the non–membrane-bound TNF-, was
collected and stored at -70°C until use. The pellets were
resuspended in PBS containing aprotinin 31 nmol/mL, PMSF 1 mmol/L,
0.1% bacitracin, and 1% Triton X-100. After 1-hour incubation at
4°C, the solubilized proteins were centrifuged for 20 minutes
at 20 000g at 4°C to remove the debris. The supernatant
contained the solubilized membrane-bound TNF-. The protein content
of the samples was measured by a Bio-Rad Protein Assay (Bio-Rad
Laboratories) with bovine serum albumin as a standard.
Quantitative expression of the membrane-bound and non–membrane-bound
TNF- was detected by a sandwich ELISA method with a mouse TNF-
DuoSet kit (Genzyme). Serum TNF- was measured similarly.
Localization of TNF- and Receptors by
Immunohistochemistry
Frozen sections of 7 mm thick were taken from the basal
surface of the distal half of the heart frozen at the time the rats
were killed. Sections were incubated with 0.3%
H2O2 in methanol for 10
minutes. After washing with H2O and PBS with
0.05% Tween-20, slides were incubated in a blocking solution (10% NGS
and 3% bovine serum albumin) for 40 minutes. The specific
primary antibody or control antibody was added to the section at a
concentration of 2 µg/mL and incubated for 2 hours at 4°C. The
rabbit anti-rat TNF- antibody was purchased from Serotec Ltd. Rabbit
anti-mouse TNF-R1/R2 polyclonal antibodies were obtained from Hycult
Biotechnology. The slides were washed with TBS-T and incubated with
goat anti-rabbit antibody conjugated to Biotin-SP for 1 hour at 4°C,
followed by incubation with peroxidase-conjugated streptavidin for 15
minutes. The slides were counterstained with 0.5% methyl green.
Statistical Analysis
All results are expressed as mean±SEM unless otherwise
specified. Statistical significance was estimated among the various
groups in TNF- production by 2-way ANOVA. Results were
considered to be significant at P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Temporal and Spatial Changes of TNF-
Gene ExpressionChanges in expression of the TNF-
gene from the infarct,
peri-infarct, and contralateral normal zones of rat heart tissue with
respect to time are illustrated in Figure 1
. Northern blot analysis
demonstrated that TNF- mRNA was consistently detectable in
the infarct, peri-infarct, and contralateral zones from infarcted
hearts, in contrast to being almost undetectable in normal control
heart (Figure 1A, lane 1). TNF- mRNA was detected at all 4
time points (days 1, 3, 10, and 35) after ligation operation; however,
there was no significant difference among the different days. Most
interestingly, the "contralateral normal zone" in the infarcted
hearts showed the highest level of TNF- expression, which did not
diminish with time after coronary ligation (Figure 1A, lanes 10 to 13). The least amount of TNF- mRNA was detected in the
peri-infarct zone (lanes 6 to 9). An intermediate amount was detected
from the infarct zone (lanes 2 to 5). The pattern was
consistently preserved in all groups, regardless of the day the
rats were killed.
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The quantitative analysis of TNF- expression in relation to
GAPDH is illustrated in Figure 1B
. The tissue from the
sham-operated groups also exhibited weak expression of TNF- mRNA at
day 1 after sham manipulation, but by day 3 and afterward, there was no
detectable expression of TNF- mRNA (data not shown). Samples were
compared with a positive control RNA from a macrophage-like
cell line, WEHI-3, stimulated with lipopolysaccharide (Figure 1A, lane 14).
To better define the localization of TNF- gene expression within
heart samples, we carried out in situ hybridization at different time
points of infarct stages by using TNF- antisense riboprobe (Figure 2, A through C). Our TNF- riboprobe
did not detect TNF- mRNA transcript in normal heart tissue (data not
shown). TNF- mRNA in in situ hybridization was identified at day 1
after infarct ligation. High levels of TNF- transcript were observed
in day 3 and day 10 (Figure 2, A and B) and persisted until day
35. The results show that the TNF- mRNA localized to the infarct,
peri-infarct, and contralateral zones (Figure 2, A and B).
Within the infarct zone, the TNF- message was identified mainly in
the infiltrating cells and endothelial cells of blood
vessels. In contrast, in the contralateral noninfarct zone, TNF-
mRNA was mainly localized to myocytes (Figure 2B). The
localization of TNF- production in myocytes was confirmed by
Masson's connective tissue staining (Figure 2C) by using
adjacent sections to differentiate fibroblasts from myocytes.
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Temporal and Spatial Changes of TNF- Protein Production
To determine whether change in TNF- mRNA transcript levels
results in change in TNF- protein production, a specific
rabbit anti-rat TNF- antibody was used for
immunostaining. The predominant area of TNF-
immunostaining localized to the infarct site and was
present at day 1 after ligation. The staining was more intense on
day 3 (Figure 2D) and day 10 after infarction and persisted
within islands of viable myocardium at day 35. Within the
infarct zone, TNF- protein was mainly localized to the inflammatory
infiltrate, vascular endothelium, and weakly to the
cardiomyocyte itself. TNF- protein was detected in the
peri-infarct zone with a similar temporal pattern, although with less
intensity than the infarct zone. Myocytes in the contralateral
noninfarct zone stained for TNF- at all time points after infarction
(Figure 2D). TNF- protein was undetectable in normal control
hearts (data not shown).
Zonal production of TNF- protein was evaluated
quantitatively by ELISA with homogenates from different
zones of rat infarcted hearts (Figure 3).
All tissue sections of the infarcted model showed an increase in
TNF- levels similar to the pattern that was observed for TNF-
gene expression. The highest levels of TNF- protein were found in
the infarct zone, with a significant 8- to 10-fold increase at all 4
different time points when the rats were killed. There is a similar 8-
to 10-fold increase of TNF- in the peri-infarct zone on days 1 and 3
but only a 3-fold increase on days 10 and 35. TNF-
production exhibited 4- to 5-fold increases in the
contralateral zone on days 1 to 10 and returned to normal at day 35. In
all animals, whether they underwent LAD ligation or sham operation,
serum TNF- was below the detectable limit of the assay (data not
shown).
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Expression of TNF- Receptor Genes and
Immunohistochemistry
Because our results showed that expression of the TNF- gene and
protein levels increased in rat infarcted heart model, we
analyzed whether there were any corresponding changes in levels
of expression of the TNF- receptor genes or their protein levels. A
single TNF-R1 mRNA transcript (Figure 4A)
and TNF-R2 mRNA transcript (Figure 4C) were detected in rat
heart by Northern blot analysis by using TNF-R1–specific and
TNF-R2–specific cDNA probes, respectively. TNF-R1 and TNF-R2 appear to
be intrinsically expressed in normal rat hearts (Figure 4A, lanes 1 and 14; Figure 4C, lane 13). Whereas the levels of
TNF-R2 mRNA transcripts in infarcted rat heart did not significantly
change compared with the normal control hearts at different
postligation time points (Figure 4C and D), expression of the
TNF-R1 mRNA transcripts in the infarct and peri-infarct zones was
upregulated during day 3 and day 10 (Figure 4A, lanes 3, 4 and
7, 8). This increase in TNF-R1 expression subsequently reduced by day
35 (Figure 4A, lanes 5 and 9).
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Immunohistochemistry results also demonstrated the expression of both
TNF-R1 (Figure 5A) and TNF-R2 (data not
shown) in heart tissues. Expression patterns for both receptors were
found to be similar, and the distribution did not change significantly
at any time period. Within the infarct zone, there was decreased
staining of TNF-R1 and TNF-R2 in the fibroblast tissue. Areas
containing endothelial and infiltrating cells showed
increased staining for both receptors. The production of
TNF-R1/R2 was clearly detected in the myocyte in the contralateral zone
by comparing it with the Masson's connective tissue staining (Figure 5B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The major new finding of this study, in which we systematically examined the spatial and temporal expression of TNF-
and TNF
receptors in the myocardium after acute ligation of the LAD
coronary artery in rats is that TNF- is persistently
expressed in the myocardium after infarction.
Interestingly, the expression of this cytokine was not confined
to the infarct zone but was persistently expressed by cardiac myocytes
in the contralateral "normal" zone, in which myocardial remodeling
was ongoing. We observed that the changes in gene expression were
mirrored by concomitant changes in protein production,
suggesting that TNF- protein biosynthesis was regulated, at least in
part, at the transcriptional level. A second new and important finding
of this study was that there was persistent expression of both
TNF-R1/R2 receptors after acute ligation of the coronary
artery, implying that the signal transduction pathways necessary for
TNF- signaling in the heart remain intact as TNF- biosynthesis
increases.
Several observations made in this study have important implications in
the understanding of cytokine contributions to heart failure.
Previously it has been thought that cytokines were mainly
produced by inflammatory cells, with the existence of TNF in the
myocardium considered mainly passive from the infiltrating
inflammatory cells.19 This was especially suggested
by observations of increased TNF- levels in conditions such as
myocarditis and Chagas' disease, with a significant known contribution
from the inflammatory processes.20 However, elevated
TNF- levels are seen in end-stage heart failure irrespective of the
cause of heart failure, and TNF- can be elevated in conditions of
hypertrophic cardiomyopathy, in which the
inflammatory component is at best minimal.21 Our study
definitely demonstrates that TNF- upregulation occurs very early
after myocardial injury and persists in myocytes with time (Figure 1). The fact that TNF- gene and protein expression is at a
high level in the contralateral zone suggests a potential role of this
cytokine in the signaling process leading to myocardial
remodeling.
Remodeling is an adaptational process of cardiac myocytes to
hemodynamic overload from various causes, such as
myocardial infarction. The ability of the heart to undergo remodeling
determines the fate of the heart to maintain the function or
decompensate. A family of matrix metalloproteinases known to digest the
fibrosis collagen matrix has been demonstrated to play an important
role in the maintenance of normal function and repairing of the
ventricular chamber in response to a superimposed
environmental stress.22 TNF- is known to
activate matrix metalloproteinases, including
collagenase type 1, stromelysin-1, and gelatinase A and
B.23 24 TNF- is also known to provoke a modest
hypertrophic growth in cardiac myocytes.6 The observations
of this present study that TNF- is produced by myocytes from the
contralateral normal zone of myocardium provide further
evidence for the role of TNF- in activation of matrix
metalloproteinases, which are capable of degrading the components of
the extracellular matrix and thereby promoting remodeling of the
ventricular chamber in response to myocardial
infarction.
Our results demonstrate that TNF- not only is present in the
myocardium during the early stages of this ligation model
but also persists well into the late stage of the
cardiomyopathy phase, when the inflammatory
components have already subsided. TNF- has been shown to induce the
injury response system, and its downstream signaling events are
implicated in the induction of apoptosis. Considering the
involvement of TNF- in apoptosis, the continued expression
in the late stages of the model has important implications. Recently,
programmed cell death has been recognized increasingly as a
contributing cause of cardiac myocyte loss in
ischemia/reperfusion injury,25 myocardial
infarction,26 vascular wall remodeling, and long-standing
heart failure.27 28 29 Furthermore, TNF- has been shown
to contribute to ongoing cell loss in the heart through stimulation of
apoptosis.7 Therefore, the persistence of TNF-
into the late stages of the infarct model may be cardiotoxic not only
from the negative inotropic effect of TNF- but from TNF-–induced
apoptosis. The local TNF- production thus should
have an important physiological effect on the
myocardial remodeling process. Indeed if TNF- is overexpressed, it
may contribute to cardiac decompensation.
We were unable to detect TNF- in the serum of any animals, ligated
or sham control, suggesting that the increased TNF- level in the
myocyte is a local phenomenon. Elevated levels of serum TNF- have
been detected in human patients with massive myocardial infarction that
eventually led to fatal cardiogenic shock.30 31 32 In our
experiments, TNF- was measured only in those animals that survived;
these animals had large but not massive infarctions. In massive
infarction, it may be that local production of TNF- is
sufficiently intense that there is spillover into the systemic
circulation accounting for the elevated serum levels. The healed
infarction/LV dysfunction model used in our experiment produces
clinical heart failure at 2 months after ligation.
Our results show that rat cardiac tissue expresses both TNF-R1 and
TNF-R2, in agreement with previous studies.33 The presence
of the TNF-R1/R2 throughout the period after infarction, including the
late stages of postinfarction in the contralateral zone, suggests that
the physiological effects of increased TNF-
production in the myocardium in the contralateral
zone will be transmitted through these receptors to the cells. Many
clinical studies have shown that the levels of circulating sTNF-R1 and
sTNF-R2 are significantly increased in advanced heart
failure.34 35 The levels of circulating sTNF-R1 and
sTNF-R2 may reflect a generalized shedding of TNF receptors from a
variety of different cell types, including the inflammatory cells.
Although our study has not clearly identified the mechanism for TNF-R1
upregulation in infarct and peri-infarct zones at day 3 and day 10, a
possible explanation is that there are changes in the types of cells
present. As we know, many cells infiltrating into the area of
tissue injury, such as polymorphonuclear leukocytes, express
high levels of TNF-R1.36 Therefore an elevation in the
number of inflammatory cells may contribute to the observed increased
level of TNF-R1 mRNA.
Conclusions
TNF protein production and gene transcription are
present in the myocardium early after myocardial
infarction in an animal model for postinfarction disease. It appears to
be a local phenomenon because serum levels were undetectable during the
time of follow-up of the animals. Expression of TNF- was found
throughout the myocardium and was detected in the
contralateral normal zone to the infarct zone. Given the known
biological effects of TNF- on the myocardium, the local
production of TNF- in the myocardium may play an
important role in ventricular dysfunction and adverse
remodeling after infarction despite the known beneficial effects of
TNF- on tissue repair after injury.37 Further study is
required to determine the signals for myocyte production of
cytokines in this disease state and to determine the changes in
TNF- gene expression and protein production as overt heart
failure develops.
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Acknowledgments |
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This study was supported in part by grants from the Heart and Stroke Foundation and Medical Research Council of Canada. Dr Peter Liu is an Endowed Research Chair of the Heart and Stroke Foundation. Dr Min Irwin is supported by a Medical Research Council fellowship award. The authors thank Dr David Irwin and Karen Aitken for critical corrections on the manuscript.
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Footnotes |
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Guest Editor for this article was Valentin Fuster, MD, PhD, Mount Sinai Medical Center, New York, NY.
Received June 4, 1998; revision received October 19, 1998; accepted November 4, 1998.
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Q. Feng, X. Lu, D. L. Jones, J. Shen, and J. M. O. Arnold Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice Circulation, August 7, 2001; 104(6): 700 - 704. [Abstract] [Full Text] [PDF]
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E. Palojoki, A. Saraste, A. Eriksson, K. Pulkki, M. Kallajoki, L.-M. Voipio-Pulkki, and I. Tikkanen Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2726 - H2731. [Abstract] [Full Text] [PDF]
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F. Wang, Y. Seta, G. Baumgarten, D. J. Engel, N. Sivasubramanian, and D. L. Mann Functional Significance of Hemodynamic Overload-Induced Expression of Leukemia-Inhibitory Factor in the Adult Mammalian Heart Circulation, March 6, 2001; 103(9): 1296 - 1302. [Abstract] [Full Text] [PDF]
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P. B. Stathopulos, X. Lu, J. Shen, J. A. Scott, J. R. Hammond, D. G. McCormack, J. M. O. Arnold, and Q. Feng Increased L-arginine uptake and inducible nitric oxide synthase activity in aortas of rats with heart failure Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H859 - H867. [Abstract] [Full Text] [PDF]
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 M. S. Lombardi, A. Kavelaars, P. M. Cobelens, R. E. Schmidt, M. Schedlowski, and C. J. Heijnen Adjuvant Arthritis Induces Down-Regulation of G Protein-Coupled Receptor Kinases in the Immune System J. Immunol., February 1, 2001; 166(3): 1635 - 1640. [Abstract] [Full Text] [PDF]
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H. Dorge, T. Neumann, M. Behrends, A. Skyschally, R. Schulz, C. Kasper, R. Erbel, and G. Heusch Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2587 - H2592. [Abstract] [Full Text] [PDF]
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D. A. Siwik, D. L.-F. Chang, and W. S. Colucci Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} Decrease Collagen Synthesis and Increase Matrix Metalloproteinase Activity in Cardiac Fibroblasts In Vitro Circ. Res., June 23, 2000; 86(12): 1259 - 1265. [Abstract] [Full Text] [PDF]
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P. M. Ridker, N. Rifai, M. Pfeffer, F. Sacks, S. Lepage, and E. Braunwald Elevation of Tumor Necrosis Factor-{alpha} and Increased Risk of Recurrent Coronary Events After Myocardial Infarction Circulation, May 9, 2000; 101(18): 2149 - 2153. [Abstract] [Full Text] [PDF]
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S. D. Prabhu, B. Chandrasekar, D. R. Murray, and G. L. Freeman {beta}-Adrenergic Blockade in Developing Heart Failure : Effects on Myocardial Inflammatory Cytokines, Nitric Oxide, and Remodeling Circulation, May 2, 2000; 101(17): 2103 - 2109. [Abstract] [Full Text] [PDF]
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D. MacKenna, S. R. Summerour, and F. J. Villarreal Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis Cardiovasc Res, May 1, 2000; 46(2): 257 - 263. [Abstract] [Full Text] [PDF]
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T. O. Nossuli, V. Lakshminarayanan, G. Baumgarten, G. E. Taffet, C. M. Ballantyne, L. H. Michael, and M. L. Entman A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1049 - H1055. [Abstract] [Full Text] [PDF]
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W. Song, X. Lu, and Q. Feng Tumor necrosis factor-{alpha} induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes Cardiovasc Res, February 1, 2000; 45(3): 595 - 602. [Abstract] [Full Text] [PDF]
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M. N. Sack, R. M. Smith, and L. H. Opie Tumor necrosis factor in myocardial hypertrophy and ischaemia -- an anti-apoptotic perspective Cardiovasc Res, February 1, 2000; 45(3): 688 - 695. [Full Text] [PDF]
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 S. D. Kim Measurement of the Renin-Angiotensin System in Heart Failure Biol Res Nurs, January 1, 2000; 1(3): 210 - 226. [Abstract] [PDF]
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S. Belosjorow, R. Schulz, H. Dorge, F. U. Schade, and G. Heusch Endotoxin and ischemic preconditioning: TNF-alpha concentration and myocardial infarct development in rabbits Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2470 - H2475. [Abstract] [Full Text] [PDF]
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D. Gurantz, R. T. Cowling, F. J. Villarreal, and B. H. Greenberg Tumor Necrosis Factor-{alpha} Upregulates Angiotensin II Type 1 Receptors on Cardiac Fibroblasts Circ. Res., August 6, 1999; 85(3): 272 - 279. [Abstract] [Full Text] [PDF]
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E. A. Palmieri, G. Benincasa, F. Di Rella, C. Casaburi, M. G. Monti, G. De Simone, L. Chiariotti, L. Palombini, C. B. Bruni, L. Sacca, et al. Differential expression of TNF-alpha , IL-6, and IGF-1 by graded mechanical stress in normal rat myocardium Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H926 - H934. [Abstract] [Full Text] [PDF]
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