(Circulation. 2001;103:1296.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Functional Significance of Hemodynamic Overload–Induced Expression of Leukemia-Inhibitory Factor in the Adult Mammalian Heart
From the Winters Center for Heart Failure Research, Department of Medicine, Houston VA Medical Center (F.W., Y.S., G.B., D.J.E., N.S., D.L.M.), and the Graduate Program in Cardiovascular Sciences, Baylor College of Medicine (F.W., D.L.M.), Houston, Tex.
Correspondence to Douglas L. Mann, MD, Cardiology Research (151C), Houston VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu
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Abstract |
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Background—Leukemia-inhibitory factor (LIF) is a member of the interleukin-6 family of cytokines that utilize gp130 as a common signaling component. In the present study, we examined the mechanisms that govern LIF expression and functional effects in the adult heart.
Methods and Results—LIF mRNA and protein biosynthesis were examined in the adult feline heart after hemodynamic overloading ex vivo. Both LIF mRNA and protein expression were detected within 60 to 90 minutes after hemodynamic overloading. Studies in isolated adult cardiac myocytes showed that these cells synthesized both LIF mRNA and protein. The functional effects of LIF in the heart were demonstrated by studies that showed that LIF stimulation led to a significant increase in general protein synthesis and an increase in sarcomeric protein synthesis. Pretreatment with LIF also protected the cells against hypoxia/reoxygenation-induced cardiac myocyte apoptosis and cellular injury. Finally, LIF had no effect on isolated cardiac myocyte cell motion.
Conclusions—Hemodynamic overload is a sufficient stimulus for LIF expression in the adult mammalian heart. Given that LIF confers both hypertrophic and cytoprotective responses in adult cardiac myocytes, this study suggests that the expression of LIF within the heart may play an important role in mediating homeostatic responses within the myocardium.
Key Words: cytokines • hemodynamics • inhibitors • myocytes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Recent studies have suggested that the gp130 signaling complex plays an important role in regulating hypertrophic and cytoprotective responses in the adult heart. For example, double transgenic mice that overexpress ligand/receptor complexes that signal through gp130 develop a concentric hypertrophic phenotype, whereas mice that harbor a ventricular-restricted deletion of gp130 undergo accelerated cardiac myocyte apoptosis after hemodynamic pressure overloading.1 2 Relevant to this discussion is the recent observation that cytokines that signal through the gp130/leukemia-inhibitory factor receptor complex, such as cardiotrophin-1 and leukemia-inhibitory factor (LIF), confer hypertrophic and cytoprotective responses in cultured neonatal cardiac myocytes.3 4 5 Moreover, LIF mRNA expression has recently been detected in the adult human heart.6 Given that LIF is expressed by a number of resident cell types within the myocardium, including endothelial cells and fibroblasts, the expression of LIF within the myocardium might provide an important autocrine/paracrine mechanism that is responsible for integrating stress responses within the heart. However, the mechanisms that govern the expression and functional effects of LIF in the adult heart are not known. Accordingly, the purpose of the present study was 2-fold: first, to determine whether hemodynamic overloading was sufficient to provoke LIF expression in the adult heart, and second, to determine the functional effects of LIF in isolated adult cardiac myocytes.
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Methods |
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Regulation of LIF Expression in the Adult Heart Ex Vivo
LIF mRNA Biosynthesis
Myocardial LIF mRNA production was assessed in freshly excised adult cat hearts with a modified Langendorff buffer (Krebs-Henseleit) perfusion apparatus.7 Hearts were either perfused at normal perfusion pressure (80 mm Hg) for 210 minutes or subjected to a brief period of hemodynamic overloading for 30 minutes (200 mm Hg), after which the perfusion pressure was returned to 80 mm Hg for an additional 180 minutes. For these studies, "time 0" refers to the time at which the elevated perfusion pressure was returned to normal (ie, 80 mm Hg). To determine the time course for LIF mRNA expression, a small sample (
500 mg) of
myocardium was excised from the suspended heart starting at time 0 and
for every 30 minutes thereafter for a total of 180 minutes (see online
supplement for details of methodology).
LIF Protein Biosynthesis
Two approaches were taken to determine LIF production
in the adult heart. First, we performed a Western blot analysis of LIF
protein from myocardial extracts from hearts perfused at normal and
elevated pressures; second, we examined LIF bioactivity in the
superfusates from the buffer-perfused hearts (see online supplement for
details).
Cellular Source for Myocardial LIF
Production
To determine whether the cardiac myocyte was a
potentially important source for LIF production, 2 different
experiments were performed. First, we examined the relative production
of LIF mRNA and protein by myocyte and nonmyocyte cell types isolated
from pressure-overloaded hearts, as we have described
previously.7 Second, we
examined LIF expression in cultured cardiac myocytes that had been
stimulated with either 200 U/mL tumor necrosis factor (TNF) or 125
µg/mL endotoxin (see online supplement for details of
methodology).
Functional Effects of LIF in Adult Cardiac
Myocytes
To determine the functional consequences of LIF
expression in the adult heart, we examined the effects of LIF on
cardiac myocyte growth and contractility (see online supplement) and
cell viability (see below).
Cytoprotective Effects of LIF
The potential cytoprotective effects of LIF were
assessed by use of a previously described model of
hypoxia/reoxygenation
injury.8 The end points for
these studies were lactate dehydrogenase (LDH) release and cardiac
myocyte apoptosis. Adult cardiac myocyte cultures (day 1) were
pretreated for 6 hours with diluent or with 10 ng/mL LIF. The myocyte
cultures were then subjected to hypoxia/reoxygenation injury, as
described previously.8 The
hypoxic conditions were maintained for 12 hours, after which the cells
were reoxygenated for 10 to 15 minutes, and the extent of cellular
injury was assessed by measurement of LDH
release8 or of the degree of
cardiac myocyte apoptosis by a modification of the recently described
in situ DNA ligation technique (see online supplement for
details).9
Mechanism for the Cytoprotective Effect of
LIF
Previous studies have shown that ligands that signal
through the LIF receptor/gp130 signaling complex confer cytoprotective
responses in neonatal cardiac myocytes through activation of the
mitogen-activated protein kinase (MAPK) (p44/p42, extracellular
signal-regulated kinase [ERK]1/ERK2) pathway and/or the Janus
kinase/signal transducer and activator of transcription (JAK/STAT)
pathway.10 11 To
determine whether the concentrations of LIF used in the present study
were sufficient to activate ERK1/ERK2 and/or STATs in adult cardiac
myocytes, we examined the degree of phosphorylation of ERK1/ERK2 and
STAT3 (a prototypical STAT), respectively (see online supplement for
details).
To determine whether MAPK inhibition was sufficient to block the functional effects of LIF in cardiac myocytes, 2 interrelated studies were conducted. First, to determine whether LIF-induced activation of ERK1/ERK2 mediated the cytoprotective effects in adult myocytes, we pretreated myocyte cultures for 30 minutes with PD98059 (1 to 10 µmol/L [Calbiochem]), a specific MAPK/ERK (MEK)1 inhibitor,12 in the presence and absence of LIF. The myocyte cultures were then subjected to hypoxia/reoxygenation injury as described above. Second, to determine whether LIF-induced activation of ERK1/ERK2 was potentially important in terms of mediating the growth-stimulatory effects in adult myocytes, we pretreated myocyte cultures for 30 minutes with PD98059 (10 µmol/L) in the presence and absence of LIF. To confirm that the concentrations of PD98059 used were sufficient to block MAPK activation, we pretreated cardiac myocytes for 30 minutes with PD98059 (10 µmol/L), in the presence and absence of 10 nmol/L angiotensin II (Sigma) for 5 minutes, insofar as PD98059 has been shown to abrogate angiotensin II–induced ERK1/ERK2 expression in isolated adult cardiac myocytes.
Statistical Analysis
Data are expressed as mean±SEM. One-way ANOVA was
used to test for mean differences in protein synthesis, LDH release,
and the extent of cardiac myocyte apoptosis; post hoc testing
(Dunnett’s or Tukey’s) was performed when appropriate. Two-way ANOVA
was used to evaluate differences between and within groups of LIF
bioassay and cell motion assay. The degree of net myosin heavy chain
and actin synthesis was analyzed by nonpaired Student’s
t
tests.
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Results |
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Regulation of LIF Expression in the Heart
LIF mRNA Biosynthesis
Figure 1A
shows that LIF mRNA was not observed from 0 to 150
minutes and was only weakly detectable at 180 minutes in the hearts
that were perfused at normal pressure. In contrast,
Figure 1B shows that LIF mRNA expression was detectable 60
to 90 minutes after hemodynamic overloading and increased thereafter
from 120 to 180 minutes. The group data summarized in
Figure 1C show that LIF mRNA expression was maximal between
120 and 150 minutes and decreased slightly by 180
minutes.
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LIF Protein Biosynthesis
Figure 2A shows that myocardial LIF was not detectable in
hearts perfused at normal pressures (data not shown). In contrast, LIF
protein levels were detectable within the myocardium as early as 60 to
90 minutes after hemodynamic overloading and increased 12-fold by
180 minutes
(Figure 2A). Consistent with the findings in myocardial
tissue, LIF bioactivity was not detectable in the superfusates from the
control hearts (n=2), whereas LIF bioactivity increased in the
superfusates from the hemodynamically overloaded hearts (n=5) within 90
minutes and continued to increase for up to 180 minutes after the
cessation of hemodynamic overloading
(Figure 2B). The specificity of the effects of LIF on M1 cell
proliferation was confirmed by use of a neutralizing anti-LIF antibody,
which completely blocked the effects of LIF on M1 cell proliferation
(see inset of
Figure 2B). One-way ANOVA indicated that there were
significant differences in LIF protein levels in the hearts subjected
to hemodynamic overloading
(P<0.001); post hoc multiple
comparison testing (Dunnett’s test) indicated that LIF protein levels
were significantly different
(P<0.05) from control at 
120
minutes.
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Cellular Source for Myocardial LIF
Production
Figure 3, A and B, shows the relative production of LIF mRNA
and protein, respectively, by cardiac myocytes and nonmyocyte cell
types in the heart after hemodynamic pressure overload. The supernatant
from the cell isolation, which is composed predominantly of nonmyocyte
cell types (>95%), expressed both LIF mRNA and protein, whereas the
cell pellets, which are composed predominantly (>95%) of cardiac
myocytes, expressed both LIF mRNA and protein. To further confirm that
isolated adult cardiac myocytes synthesized LIF, we stimulated adult
cardiac myocyte cultures with TNF (200 U/mL) and endotoxin (125
µg/mL).
Figure 3C shows that the level of mRNA expression was
minimal in diluent-treated myocyte cultures, whereas LIF mRNA
expression increased 5.5- and 11-fold, respectively, after
stimulation with TNF or endotoxin.
Figure 3B shows that LIF protein levels were barely
detectable in the diluent-treated cultures, whereas they were increased
3.8-fold (for both) after treatment with TNF or endotoxin. Each of
the above experiments was confirmed in 2 additional
experiments.
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Functional Effects of LIF in Adult Cardiac
Myocytes
We examined the effects of LIF on cardiac myocyte
hypertrophy and cell motion. In brief, these studies showed that LIF
increased general protein synthesis (Figure
IA) and sarcomeric protein
synthesis (Figure IB) in cultured adult cardiac myocytes, whereas LIF
had no effect (Figure II) on isolated cardiac myocyte contractility
(presented in full in the online supplement). The effects of LIF on
cardiac myocyte viability after hypoxia/reoxygenation injury are
presented below.
Cytoprotective Effects of LIF: LDH
Release
Figure 4 shows 3 important findings with respect to the
cytoprotective effects of LIF. First, there was no significant
difference in LDH release in the diluent-treated (n=32 cultures) and
LIF-stimulated (10 ng/mL; n=12 cultures) cultures studied under
normoxic conditions. Second, hypoxia/reoxygenation resulted in a
significant 2-fold increase in LDH release in diluent-treated cardiac
myocyte cultures (n=27 cultures) compared with diluent-treated normoxic
cardiac myocyte cultures, consistent with our earlier
observations.8 Third, LIF (10
ng/mL) pretreatment significantly attenuated LDH release compared with
diluent-treated hypoxic myocyte cultures (n=27 cultures). As shown in
Figure 4, however, the degree of LDH release in LIF-treated
hypoxic cells was still significantly greater than that observed in
diluent-treated normoxic cells, suggesting that LIF did not completely
protect the myocytes from hypoxia/reoxygenation injury
(P<0.05). Importantly, the
cytoprotective effects of LIF were abrogated completely by an anti-LIF
antibody (n=9 cultures). One-way ANOVA indicated that there were
significant overall differences between groups
(P<0.001); post hoc ANOVA
testing (Tukey) indicated that there were no significant differences in
LDH release in normoxic cells in the presence and absence of LIF
(P>0.05), whereas there was a
significant increase in LDH release in normoxic compared with hypoxic
cells (P<0.01) and a
significant decrease in LDH release in LIF-treated hypoxic cells
compared with diluent-treated hypoxic cells
(P<0.01).
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Cytoprotective Effects of LIF: Cardiac Myocyte
Apoptosis
Figure 5, A and B, shows representative examples of DNA
labeling in normoxic and hypoxic cardiac myocyte cultures,
respectively.
Figure 5C shows a pattern of diffuse nuclear staining that
is observed with the in situ DNA ligation technique after DNase I
treatment (positive control). The group data depicted in
Figure 5D show that the extent of DNA labeling in
diluent-treated normoxic cardiac myocyte cultures (n=6) was
3.3±0.5%. Hypoxia/reoxygenation injury led to a significant 2-fold
increase in DNA labeling in the myocyte cultures (n=6), whereas
pretreatment with LIF resulted in an 30% reduction in the number of
apoptotic cardiac myocytes (n=6 cultures). It should be noted, however,
that the frequency of apoptosis noted in the control cultures was in
excess of that observed in normal myocardium, consistent with the
findings reported by others in cultured adult
myocytes.13 Accordingly, we
cannot exclude the possibility that the degree of reduction of
LIF-induced apoptosis in the cultured cells might be less in myocardial
tissue. One-way ANOVA indicated that there were overall significant
differences between groups
(P<0.001); post hoc ANOVA
testing (Tukey) indicated that there was a significant increase in the
number of apoptotic myocytes in the diluent-treated hypoxic myocytes
compared with diluent-treated normoxic myocytes
(P>0.05) and that there was a
significant decrease in myocyte apoptosis in the LIF-treated hypoxic
cardiac myocytes compared with diluent-treated hypoxic myocytes
(P<0.01); the level of
apoptosis in the LIF-pretreated hypoxic/reoxygenation cells, however,
was still significantly greater
(P<0.05) than that observed in
normoxic control cells.
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Mechanism for the Cytoprotective Effect of
LIF
In preliminary control experiments, we established that
stimulation with LIF provoked a concentration-dependent increase in
ERK1/ERK2 phosphorylation
(Figure 6A) and STAT3 phosphorylation on serine 727 and
tyrosine 705
(Figure 6B). To determine whether MEK1 inhibition was
sufficient to block the effects of LIF on MAPK and/or STAT3
phosphorylation, we repeated the above assays after pretreatment with
PD98059 (1 to 10 µmol/L). As shown in
Figure 6A, PD98059 inhibited MAPK phosphorylation in a
dose-dependent manner; at 1 µmol/L, we observed partial attenuation,
whereas at 10 µmol/L, we observed complete attenuation of ERK1/ERK2
phosphorylation. As an additional control experiment, we showed that
PD98059 (10 µmol/L) abrogated angiotensin II–induced ERK1/ERK2
activation
(Figure 6A), as has been reported previously.
Figure 6, B and C, shows that pretreatment with
PD98059 resulted in a significant decrease in phosphorylation of STAT3
on serine 727, suggesting that there is cross-talk between the MAPK and
JAK/STAT pathways. In contrast, PD98059 had no significant effect of
the degree of phosphorylation on tyrosine 705. Finally, to determine
whether inhibition of ERK1/ERK2 activity would attenuate the
cytoprotective effects of LIF, we pretreated the cells with 10 µmol/L
PD98059 before LIF stimulation.
Table 1 shows that pretreatment with 10 µmol/L
PD98059 resulted in a complete loss of the cytoprotective effects of
LIF, both in terms of preventing LDH release
(P<0.05) and cardiac myocyte
apoptosis (P<0.05).
Importantly, PD98059 (10 µmol/L) had no significant effect on LDH
release or the rates of cardiac myocyte apoptosis in both normoxic and
hypoxic conditions, suggesting that the observed effects of PD98059
were not secondary to nonspecific cytotoxic effects of this compound.
Table 2 further shows that pretreatment with PD98059 led to
a significant decrease
(P<0.05) in LIF-induced
protein synthesis compared with cells that had been stimulated with LIF
alone. The extent of protein synthesis in the LIF-stimulated cells that
had been pretreated with PD98059, however, was still significantly
greater than that in diluent-treated cells
(P<0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of this study, in which we examined the expression and functional significance of leukemia-inhibitory factor (LIF) in the adult mammalian heart, permit several new and potentially important insights to be drawn with respect to the biological role that LIF plays in the adult heart. First, both LIF mRNA (Figure 1B
) and protein
(Figure 2, A and B) are rapidly synthesized within the adult
heart in response to a superimposed environmental stress, such as
hemodynamic overloading. The observation that LIF mRNA and protein were
synthesized by adult cardiac myocytes and nonmyocytes
(Figure 3) suggests that LIF may play an important
autocrine/paracrine signaling role in the heart. Second, LIF-mediated
signaling conferred both hypertrophic (Figure I) and cytoprotective
(Figures 4 and 6D) responses in isolated adult cardiac
myocytes that had been subjected to hypoxia/reoxygenation injury.
Moreover, these hypertrophic and cytoprotective responses occurred in
the absence of any discernable deleterious short-term effects on
isolated cardiac myocyte cell motion (Figure II), as have been reported
for interleukin-6.14 Thus,
the pattern of expression of LIF in response to a superimposed
environmental stress and the salutary functional effects of LIF in
cardiac myocytes suggest that the stress-induced expression of LIF
within the myocardium may play an important role in mediating
homeostatic responses within this tissue.
Biological Effects of LIF in Cardiac
Myocytes
Although the functional significance of LIF-mediated
signaling in the adult myocyte has not been studied heretofore,
previous studies in neonatal cardiac myocytes suggest that LIF
stimulation increases the rate of general protein
synthesis.4 5 15
Thus, the findings in the present study both confirm and expand on
these observations in neonatal cells by demonstrating that stimulation
with LIF stimulation provokes an increase in sarcomeric protein
synthesis (Figure IB). Moreover, the results of the present study
suggest that the LIF-mediated increase in protein synthesis is
partially sensitive to PD98059, a MEK1 inhibitor
(Table 2). That is, there was a significant decrease in
protein synthesis in the LIF-stimulated cells that had been pretreated
with PD98059
(Table 2). It is not possible, however, to determine from
the present studies whether the MAPK and/or JAK/STAT pathway was
responsible for the hypertrophic effects of LIF, insofar as PD98059
significantly inhibited the phosphorylation of both MAPK and STAT3
phosphoproteins.
The findings in the present study that LIF protects isolated
cardiac myocytes against hypoxia/reoxygenation-induced injury
(Figures 4 and 6 and
Table 1) are consistent with previous reports that showed
that LIF confers cytoprotective responses in isolated myocytes and
intact myocardial
tissue.10 16 For
example, a previous study in neonatal cells suggested that the
cytoprotective/antiapoptotic effects of LIF are mediated through
JAK/STAT-induced upregulation of
Bcl-xL.10 Although we cannot
formally exclude a potential role for LIF-induced upregulation of
Bcl-xL in adult myocytes, our results suggest that the cytoprotective
effects of LIF are mediated through activation of the MAPK pathway and
are thus consistent with a previous study that showed that activation
of the MAPK pathway was required for the cytoprotective effects of
cardiotrophin-1.11
Nonetheless, given that treatment with PD98059 resulted in decreased
phosphorylation of STAT3, we cannot formally exclude the interesting
possibility that cross-talk between the MAPK and JAK/STAT pathways may
be responsible, at least in part, for the cytoprotective effects of
LIF.
Conclusions
The observation that myocyte and nonmyocyte cell types
synthesize a variety of "homeostatic proteins" in response to a
superimposed environmental stress is certainly not new and was first
suggested by a series of insightful experimental studies nearly 20
years ago.17 Recent studies
from a number of different laboratories have also shown that an
ensemble of stress-activated cytokines, including TNF, interleukin-1
and -6, and
cardiotrophin-1,18 19 20
are expressed within the myocardium after hemodynamic overloading
and/or ischemic injury. Although the precise role that these
stress-activated cytokines play in the myocardium is unclear, there is
now increasing evidence that suggests that the short-term expression of
these molecules may play a critical role in initiating and integrating
the myocardial response to a superimposed environmental stress. The
findings in the present study are entirely consistent with this point
of view and suggest that LIF may play an important autocrine/paracrine
role in mediating both short-term and longer-term myocardial responses
to environmental stress, both by preventing cardiac myocyte apoptosis
and by stimulating hypertrophic cardiac myocyte growth. Accordingly, it
will be important in future studies to determine whether selective
activation of this pathway will confer adaptive myocardial responses in
vivo.
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Acknowledgments |
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This research was supported by research funds from the NIH (P50-HL-O6H, RO1-HL-58081-01, RO1-HL-61543-01, and HL-42250-10/10). The authors gratefully acknowledge Dr Colin L. Stewart, who kindly provided us with the human LIF cDNA, and the technical assistance of Dorellyn Lee-Jackson and Stacey Walker. We would also like to thank Dr Andrew I. Schafer for his past and present support and guidance.
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Footnotes |
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Figures I and II and Supplementary Material can be found online at www.circulationaha.org.
Guest Editor for this article was Peter P. Liu, MD, FRCPC, FACC, Toronto Hospital, Toronto, Ontario, Canada.
Received May 30, 2000; revision received September 14, 2000; accepted September 15, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Hirota H, Yoshida K, Kishimoto T, et al. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci U S A. 1995;92:4862–4866.
2. Hirota H, Chen J, Betz UA, et al. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1999;97:189–198.[Medline] [Order article via Infotrieve]
3.
Wollert KC, Taga T,
Saito M, et al. Cardiotrophin-1 activates a distinct form of cardiac
muscle cell hypertrophy. J Biol
Chem. 1996;271:9535–9545.
4. Matsui H, Fujio Y, Kunisada K, et al. Leukemia inhibitory factor induces a hypertrophic response mediated by gp130 in murine cardiac myocytes. Res Commun Mol Pathol Pharmacol. 1996;93:149–162.[Medline] [Order article via Infotrieve]
5.
Oh H, Fujio Y,
Kunisada K, et al. Activation of phosphatidylinositol 3-kinase through
glycoprotein 130 induces protein kinase B and p70 S6 kinase
phosphorylation in cardiac myocytes.
J Biol Chem. 1998;273:9703–9710.
6.
Cullinan EB,
Abbondanzo SJ, Anderson PS, et al. Leukemia inhibitory factor (LIF) and
LIF receptor expression in human endometrium suggests a potential
autocrine/paracrine function in regulating embryo implantation.
Proc Natl Acad Sci
U S A. 1996;93:3115–3120.
7.
Kapadia S, Oral H,
Lee J, et al. Hemodynamic regulation of tumor necrosis factor-
gene
and protein expression in adult feline myocardium.
Circ Res. 1997;81:187–195.
8.
Nakano M, Mann DL,
Knowlton AA. Blocking the endogenous increase in HSP 72 increases
susceptibility to hypoxia and reoxygenation in isolated adult feline
cardiocytes. Circulation. 1997;95:1523–1531.
9. Didenko VV, Tunstead JR, Hornsby PJ. Biotin-labeled haripin oligonucleotides: probes to detect double-strand breaks in DNA apoptotic cells. Am J Pathol. 1998;152:897–902.[Abstract]
10. Fujio Y, Kunisada K, Hirota H, et al. Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. J Clin Invest. 1997;99:2898–2905.[Medline] [Order article via Infotrieve]
11.
Sheng Z, Knowlton
K, Chen J, et al. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte
apoptosis via a mitogen-activated protein kinase-dependent pathway.
J Biol Chem. 1997;272:5783–5791.
12.
Dudley DT, Pang
L, Decker SJ, et al. A synthetic inhibitor of the mitogen-activated
protein kinase cascade. Proc Natl Acad Sci
U S A. 1995;92:7686–7689.
13.
Communal C, Singh
K, Pimentel DR, et al. Norepinephrine stimulates apoptosis in adult rat
ventricular myocytes by activation of the ß-adrenergic pathway.
Circulation. 1998;98:1329–1334.
14.
Finkel MS, Oddis
CV, Jacob TD, et al. Negative inotropic effects of cytokines on the
heart mediated by nitric oxide.
Science. 1992;257:387–389.
15.
Kodama H, Fukuda
K, Pan J, et al. Leukemia inhibitory factor, a potent cardiac
hypertrophic cytokine, activates the JAK/STAT pathway in rat
cardiomyocytes. Circ Res. 1997;81:656–663.
16. Nelson SK, Wong GHW, McCord JM. Leukemia inhibitory factor and tumor necrosis factor induce manganese superoxide dismutase and protect rabbit hearts from reperfusion injury. J Mol Cell Cardiol. 1995;27:223–229.[Medline] [Order article via Infotrieve]
17.
Hammond GL,
Wieben E, Markert CL. Molecular signals for initiating protein
synthesis in organ hypertrophy. Proc Natl
Acad Sci
U S A. 1979;76:2455–2459.
18.
Gwechenberger M,
Mendoza LH, Youker KA, et al. Cardiac myocytes produce interleukin-6 in
culture and in viable border zone of reperfused infarctions.
Circulation. 1999;99:546–551.
19.
Irwin MW, Mak S,
Mann DL, et al. Tissue expression and immunolocalization of tumor
necrosis factor- in postinfarction dysfunctional myocardium.
Circulation. 1999;99:1492–1498.
20. Herskowitz A, Choi S, Ansari AA, et al. Cytokine mRNA expression in postischemic/reperfused myocardium. Am J Pathol. 1995;146:419–428[Abstract]
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M. Flesch, A. Hoper, L. Dell'Italia, K. Evans, R. Bond, R. Peshock, A. Diwan, T. A. Brinsa, C.-C. Wei, N. Sivasubramanian, et al. Activation and Functional Significance of the Renin-Angiotensin System in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor Circulation, August 5, 2003; 108(5): 598 - 604. [Abstract] [Full Text] [PDF]
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 E. A. Kritikou, A. Sharkey, K. Abell, P. J. Came, E. Anderson, R. W. E. Clarkson, and C. J. Watson A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland Development, August 1, 2003; 130(15): 3459 - 3468. [Abstract] [Full Text] [PDF]
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