Institut National de la Santé et de la Recherche Médicale Unité 99, Hôpital Henri Mondor, 94010 Créteil, France
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ABSTRACT |
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Tumor necrosis
factor (TNF)- has a biphasic effect on heart contractility and
stimulates phospholipase A2 (PLA2) in
cardiomyocytes. Because arachidonic acid (AA) exerts a dual effect on
intracellular Ca2+ concentration
([Ca2+]i) transients, we investigated the
possible role of AA as a mediator of TNF-
on
[Ca2+]i transients and contraction with
electrically stimulated adult rat cardiac myocytes. At a low
concentration (10 ng/ml) TNF-
produced a 40% increase in the
amplitude of both [Ca2+]i transients and
contraction within 40 min. At a high concentration (50 ng/ml) TNF-
evoked a biphasic effect comprising an initial positive effect peaking
at 5 min, followed by a sustained negative effect leading to
50-40% decreases in [Ca2+]i transients
and contraction after 30 min. Both the positive and negative effects of
TNF-
were reproduced by AA and blocked by arachidonyltrifluoromethyl
ketone (AACOCF3), an inhibitor of cytosolic PLA2.
Lipoxygenase and cyclooxygenase inhibitors reproduced the high-dose
effects of TNF-
and AA. The negative effects of TNF-
and AA were
also reproduced by sphingosine and were abrogated by the ceramidase
inhibitor n-oleoylethanolamine. These results point out the
key role of the cytosolic PLA2/AA pathway in mediating the
contractile effects of TNF-
.
heart; cytosolic Ca2+-dependent phospholipase A2; ceramidase; sphingosine
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INTRODUCTION |
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TUMOR NECROSIS
FACTOR (TNF)- is a proinflammatory cytokine with
pleiotropic effects, initially described as a lipopolysaccharide (LPS)-induced macrophage product. Whereas there is no constitutive expression of the TNF-
gene in normal heart, TNF-
is produced by
various cardiac cell types, including cardiomyocytes, in response to
stressful stimuli (9, 16). Several studies have shown a
negative inotropic effect of TNF-
(1, 10, 11, 24, 26,
42) associated with alterations in Ca2+ homeostasis
(42), sphingosine production (26), and
inducible nitric oxide synthase induction (1). In
animal models, whether administered by peritoneal infusion
(3) or overexpressed by cardiomyocytes (4, 8,
18), TNF-
causes severe heart dysfunction, the rate of
progression and severity of which depend on the degree of TNF-
overexpression (8). This is relevant to observations that,
in human subjects, high levels of this circulating cytokine, and/or its
high expression in the myocardium, are causally linked to the
progression of dilated cardiomyopathy (12, 19, 30, 39).
Contrary to these deleterious effects on heart contraction observed at
high concentrations, Mann and collaborators (25) reported
that, at low concentrations, TNF- may have an important autocrine
and/or paracrine homeostatic role in the heart. This is supported by
the observations that TNF-
1) protects against hypoxic
injury (25), 2) induces hypertrophic growth
(41), and 3) has a positive inotropic effect on
heart contractility in conscious dogs (24). The signaling
pathways involved in the effects of TNF-
remain obscure.
In various cell types, including cardiomyocytes, TNF- increases
arachidonic acid (AA) release through phospholipase A2
(PLA2) activation (22). AA is a major
polyunsaturated fatty acid in cellular membranes. It plays a unique
role relative to other fatty acids because it can be metabolized to
various cardioactive compounds, including prostanoids via the
cyclooxygenase (COX) pathway, leukotrienes via the lipoxygenase (LOX)
pathway, and epoxyeicosatrienioic acids via the cytochrome
P-450 pathway (for review, cf. Ref. 40). AA
itself can be a potent intracellular second messenger. In
cardiomyocytes it modulates a variety of systems, including ion
channels, gap junctions, and protein kinase C (PKC) activity (for
review, cf. Ref. 28). We previously demonstrated the role
of AA as a second messenger in the positive effects of
glucagon/miniglucagon (32, 33) and
2-adrenergic agonists (23, 27).
Although AA release induced by TNF- has been linked to biological
effects in other cell types, this question has not been specifically
addressed in cardiomyocytes. Indeed, previous studies have examined
either the effects of TNF-
on AA release, intracellular Ca2+ concentration ([Ca2+]i)
transients, and/or cardiac function or those of AA on contraction and/or [Ca2+]i transients (5, 13, 15,
27, 33). The aim of the present study was to reproduce the
effects of TNF-
on heart contraction, which were previously
described in conscious dogs (24) and the perfused isolated
heart (42), in isolated cardiomyocytes obtained from adult
animals, to examine the possible role of AA as a trigger of
TNF-
-induced [Ca2+]i transient and
contractile responses.
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METHODS |
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Cardiomyocyte isolation. Adult male Wistar rats weighing 180-250 g (Janvier, Le Genest St Isle, France) were used. Calcium-tolerant myocytes were isolated by cardiac retrograde aortic perfusion as described by Delcayre et al. (6).
Measurement of [3H]AA release.
AA release was determined as previously described (27) by
measuring [3H]AA release into the surrounding medium from
cardiomyocytes previously labeled with [3H]AA. Briefly,
freshly isolated cardiomyocytes were suspended in complete BM86 (BM86
Wissler medium supplemented with 100 IU/ml penicillin, 0.1 µg/ml
streptomycin, 4 µg/ml insulin, 20 µg/ml holotransferrin, and 1 mM
glutamine), plated in 24-well plates previously coated with 3 µg/ml
laminin (105 rod-shaped cells/ well in 2 ml complete BM86),
and left in humidified 5% CO2-95% air at 37°C. After
2 h, the cell medium was replaced by 2 ml of complete BM86 with 1 µCi/ml [3H]AA (4.5 nM). After 24-h incubation, cells
were washed twice with 2 ml of complete BM86 with 0.2% fatty acid-free
serum albumin, twice with 2 ml of HEPES buffer [in mM: 130 NaCl, 4.8 KCl, 1.2 KH2PO4, 25 HEPES, pH 7.4, 5 D(+)-glucose] with 0.2% fatty acid-free serum albumin,
and once with 2 ml of HEPES buffer. When stated, [3H]AA-labeled cardiomyocytes were preincubated for 15 min with or without 10 µM arachidonyltrifluoromethyl ketone
(AACOCF3). At time 0 of the experiment, cells were exposed
to TNF- or vehicle for 10 or 20 min at 37°C. Incubation was
terminated by the addition of ice-cold EGTA (4 mM final), and cell
medium was immediately transferred to microcentrifuge tubes. After
centrifugation at 17,600 g for 20 min at 4°C, the amount
of radioactivity in the supernatants was quantitated by liquid
scintillation counting.
Measurement of [Ca2+]i transients and cell fractional shortening. Freshly isolated cardiomyocytes were plated on plastic dishes, on the bottom of which was placed a glass coverslip coated with 2 µg/ml laminin (105 rod-shaped cells/dish in 2 ml HEPES buffer containing 2% bovine serum albumin), and were incubated at 37°C in humidified 5% CO2-95% air for 1.5-3 h. Cells, attached to laminin, were bathed in 2 ml of saline buffer A (in mM: 10 glucose, 130 NaCl, 5 KCl, 10 HEPES buffered at pH 7.4 with Tris base, 1 MgCl2, 2 CaCl2) and were incubated for 20 min at 25°C with 1.5 µM fura 2-AM in the presence of 0.1% bovine serum albumin to improve fura 2 dispersion and facilitate cell loading. Cells were then washed twice with saline buffer A. Field electrical stimulation (square waves, 10-ms duration, 0.5 Hz) was supplied through a pair of platinum electrodes connected to the output of a HAMEG stimulator (Paris, France). Ca2+ imaging (IMSTAR, Paris, France) was performed as described by Sauvadet et al. (31). [Ca2+]i transients were represented as fluorescence ratios (F360/F380). Cell fractional shortening was determined from the fluorescence images recorded to measure F360/F380 with Scion Image software (Scion, Frederick, MD). All tracings of fluorescence ratios and fractional shortenings are representative of 6-10 cells obtained from three different isolations.
Statistical analysis. Data are expressed as means ± SE. Results were analyzed by using Student's two-tailed t-test or repeated-measures ANOVA and post hoc multiple-comparison testing between control and treatment groups (Dunnett's test), as appropriate. Differences were considered statistically significant at P < 0.05.
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RESULTS |
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TNF- exerts dual effect on
[Ca2+]i transients and
contraction in electrically stimulated adult rat ventricular myocytes.
Perfusion of electrically stimulated cardiomyocytes with TNF-
for 40 min produced a concentration-dependent dual effect on [Ca2+]i transients (Fig.
1). At a low concentration (10 ng/ml),
TNF-
produced an overall 32 ± 10% increase over control in
amplitude of [Ca2+]i transients (taking into
account all cells). In contrast, at a high concentration (50 ng/ml),
TNF-
caused a 40 ± 10% reduction in the amplitude of
[Ca2+]i transients relative to control
(taking into account all cells).
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Dual effect of TNF- requires cytosolic
Ca2+-dependent PLA2
activation.
Liu and McHowat (22) reported a dose-dependent activation
of AA release by TNF-
in adult rat cardiomyocytes. In keeping with
this finding, exposure to 50 ng/ml TNF-
of cardiomyocytes labeled
overnight with [3H]AA resulted in a significant threefold
increase over baseline [3H]AA release within 10 min (Fig.
4A; n = 5;
P < 0.05). Total [3H]AA remained
significantly higher than baseline throughout 20 min of exposure to
TNF-
(6-fold increase; n = 5; P < 0.05). AACOCF3, a widely used specific inhibitor of cytosolic
Ca2+-dependent PLA2 (cPLA2)
(36), completely blocked TNF-
-induced [3H]AA release when added to the cell medium at a
concentration of 10 µM 15 min before TNF-
(Fig. 4A). Thus, to
assess the possible involvement of the cPLA2/AA pathway in
the effects of TNF-
on [Ca2+]i transients
and contraction, we examined the effect of AACOCF3 in electrically
stimulated cardiomyocytes. AACOCF3 (10 µM) had no effect by itself
but abrogated both the positive and negative effects of 10 and 50 ng/ml
TNF-
, respectively, on [Ca2+]i transients
and contraction (Fig. 4B).
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AA reproduces dual effect of TNF- on
[Ca2+]i transients and
contraction in electrically stimulated cardiomyocytes.
The time-dependent effect of increasing concentrations of AA added to
the perfusion medium on [Ca2+]i transients of
electrically stimulated adult rat cardiomyocytes was examined next
(Fig. 5). AA concentrations up to 3 µM
had no significant effect (Fig. 5A). With 5 µM AA (Fig.
5B) a sustained increase in the amplitude of
[Ca2+]i transients and contraction was
observed in 6 of 11 cells (+30-40% after 20 min), whereas a
transitory increase occurred in 1 cell (+20-25% at 5 min) and a
biphasic effect was observed in 4 cells (10-20% activation at 5 min followed by a progressive depression reaching 40-50% below
control values at 30 min). As shown in Fig. 5C, with 10 µM
AA a sustained increase in the amplitude of
[Ca2+]i transients and contraction was
observed in only 8 of 21 cells (+40-45% at 30 min) whereas 3 cells displayed transitory positive responses (+15-20% at 5 min)
and 10 cells responded in a biphasic way (15-20% activation at 5 min followed by a progressive depression reaching 40-50% below
control values at 30 min). At the highest concentration of AA tested
(25 µM), half of the cells displayed a transitory positive response
(+10-15% at 5 min) whereas the other half of the cells displayed
a biphasic response (+15-20% at 5 min followed by a progressive
depression reaching 50-60% below control values at 30 min). The
typical traces of [Ca2+]i transients and cell
fractional shortening in Fig. 6 further illustrate the correlation between the increases and decreases in
[Ca2+]i transients and contraction. It should
be noted that AACOCF3, when added to the cell medium 15 min before AA,
affected neither the positive nor the negative effect of AA at 10 and
25 µM, respectively.
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Negative effects of TNF- and AA on
[Ca2+]i transients and
cardiomyocyte contractility require ceramidase activation.
It has been reported that sphingosine mediates the negative inotropic
effect of TNF-
on adult feline cardiac myocytes (26). As shown in Fig. 8, within 30 min,
exogenous sphingosine exerted a dose-dependent depressant effect on
[Ca2+]i transients and contraction: 1 µM
sphingosine elicited 25 ± 4% and 28 ± 5% inhibition,
respectively, whereas 10 µM sphingosine produced a total inhibition
of both [Ca2+]i transients and contraction in
six of seven cells, thus mimicking the negative effects of 25 µM AA
and 50 ng/ml TNF-
. We next examined whether
n-oleoylethanolamine (NOE), a specific ceramidase inhibitor that converts ceramide to sphingosine, could abrogate the effects of
TNF-
and AA on [Ca2+]i transients and
contraction. Cardiomyocytes were preincubated for 30 min with buffer,
with or without 1 µM NOE, and exposed thereafter for 30 min to 50 ng/ml TNF-
or 25 µM AA, added in combination with or without 1 µM NOE. As shown in Fig. 8, treatment with NOE abrogated the global
negative effects of both 25 µM AA and 50 ng/ml TNF-
on
[Ca2+]i transients and cell contraction. An
important finding was that NOE unmasked the positive effects on
[Ca2+]i transients and contraction of 25 µM
AA and 50 ng/ml TNF-
. In the presence of NOE, 40% and 50% of the
cells responded positively to 25 µM AA and 50 ng/ml TNF-
,
respectively. It should also be noted that NOE, by itself, had a
statistically significant positive effect on the amplitude of
[Ca2+]i transients and contraction: 34 ± 7% and 30 ± 7%, respectively (P < 0.05;
Fig. 8). An attractive explanation is that, in control conditions,
because of ceramidase activity, sphingosine is produced in a quantity
large enough to exert a negative constraint on
[Ca2+]i transients and contraction, which is
relieved on inhibition of ceramidase.
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DISCUSSION |
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These results show that TNF- exerts a time- and
concentration-dependent dual tuning effect on
[Ca2+]i transients and contraction of
electrically stimulated adult rat cardiomyocytes. The following
observations suggest that AA, produced by cPLA2 activation,
mediates these early contractile effects of TNF-
. 1)
TNF-
increases AA release from [3H]AA-prelabeled
cardiomyocytes, and this effect is blocked by AACOCF3, a specific
cPLA2 inhibitor. 2) Both the stimulatory and depressant effects of TNF-
on [Ca2+]i
transients and contraction are inhibited by AACOCF3. 3) AA, added exogenously to the perfusion medium, reproduces the effects of
TNF-
on [Ca2+]i transients and contraction.
Negative or positive effects of AA on [Ca2+] transients of electrically stimulated or spontaneously beating cardiomyocytes have been observed in various settings. Hoffmann et al. (13) described a cessation of electrically induced [Ca2+]i transients in electrically stimulated neonatal rat cardiomyocytes after exposure to AA (10-30 µM). Conversely, Damron and Summers (5) described a positive effect of AA (10-50 µM) on the amplitude of [Ca2+]i transients in electrically stimulated adult rat cardiomyocytes. In fact, the dual action of AA observed in the present study is particularly reminiscent of that described by Kang and Leaf (15). These authors reported that perfusion of spontaneously beating neonatal rat cardiomyocytes with 5-10 µM AA had different effects on the rate of contraction (increase, decrease, or no change) and proposed that differences in the individual sensitivity of cardiomyocytes to AA could be due to differences in lipid metabolic status.
TNF- is produced by the heart in cardiac pathophysiological contexts
(2, 35, 38). However, only concentrations of TNF-
in
the plasma (3-9 ng/ml) have been determined (2, 7, 37), and according to Torre-Amione et al. (37),
there is no tight correlation between those concentrations and the
cytokine levels in heart tissue. Thus we examined the effect of TNF-
on isolated cardiomyocytes at concentrations ranging from 2.5 to 50 ng/ml, similar to those used in different studies that dealt with
various effects of TNF-
in isolated cardiomyocytes: the effects of
TNF-
on hypoxic injury and on the hypertrophic growth response in
isolated adult feline cardiomyocytes were examined at 10-1,000
U/ml, i.e., 0.5-50 ng/ml (25, 41), activation of
PLA2 was examined with 2.5-50 ng/ml (22),
and the apoptotic effect was examined with
4,000 U/ml, i.e., 90 ng/ml TNF-
concentrations (17). The use of such
concentrations is compatible with the dissociation constant
(Kd) of TNF-
receptors: 0.3 nM, i.e., 5 ng/ml
(38).
The depressant effect triggered by high concentrations of either AA or
TNF- observed here is reproduced by inhibitors of the AA metabolic
pathways, LOX and COX. This suggests that AA itself, rather than a
metabolic product, was involved in this effect. In addition, we show
that the depressant effects of TNF-
and AA are reproduced by
treating cardiomyocytes with 1-10 µM sphingosine. Conversely,
they are blocked by NOE, a specific inhibitor of ceramidase that
converts ceramide to sphingosine. Those findings are in agreement with
the previous statement that, in adult cardiomyocytes, sphingosine
mediated the negative contractile effect of TNF-
and designate the
target of AA upstream of sphingosine generation. Ceramidase has not
been identified as a target for AA. In contrast, the neutral
sphingomyelinase, which converts sphingomyelin to ceramide, is
activated by AA (14, 29) and therefore represents an
attractive candidate.
We show here that the positive contractile effects of AA and TNF-
are largely favored in blockade of the ceramidase pathway. The question
as to whether the positive effect of AA on
[Ca2+]i transients and contraction is
mediated by AA itself or by metabolites has been answered by a previous
study that focused on the positive effect of AA (5, 22).
Those authors concluded that the positive effect of AA on
[Ca2+]i transients and contraction was
mediated partly by AA itself and in part by COX metabolites and would
involve PKC-dependent inhibition of voltage-gated K+
channels. In previous studies (23, 33), we also showed
that AA causes Ca2+ accumulation in the sarcoplasmic
compartment sensitive to caffeine, a mechanism likely to support
positive inotropy.
Thus, to summarize, the effects of AA on [Ca2+]i transients and contraction combine 1) a positive effect predominating at low AA concentrations and 2) a negative effect that prevails with increasing AA concentrations. The relative activation of the positive and negative pathways determines the nature of the final response.
The negative contractile effect of TNF- is one of its major
pathogenic effects. The present study identifies AA as a mediator of
this effect, presumably upstream of the ceramidase cycle. Future studies will be designed to evaluate the possible role of the neutral
sphingomyelinase as the target of AA (14). Interestingly, Liu and Hannun and coworkers (20, 21) showed that
physiological levels of glutathione inhibit the neutral
sphingomyelinase activity. Thus one can speculate that the cellular
level of glutathione is a determinant component in the contractile
response to TNF-
. Additional studies are required to determine
whether manipulating intracellular glutathione levels affects the
response of isolated cardiomyocytes to AA and TNF-
and whether this
extends to the whole heart in the animal. It should be noted that
variations in the cellular glutathione levels of isolated
cardiomyocytes could underlie the divergence of cell responses observed
in the present study.
In conclusion, our results show that the positive and negative effects
of TNF- on heart contraction are mediated by cPLA2 activation and AA release. Although short-term effects in
isolated cells cannot be directly extrapolated to long-term phenomena
occurring in the heart in vivo, this study also raises the possibility
that cPLA2 activation and AA may be major pathogenic and/or
protective components of heart functioning depending on the oxidative
and metabolic status of the cardiomyocytes.
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ACKNOWLEDGEMENTS |
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We thank M. Lebec for expert computing skills, S. Lotersztajn, N. Defer, G. Guellaën, and Y. Laperche for helpful discussions, and J. Hanoune for permanent support.
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FOOTNOTES |
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This work was supported by the Institut National de la Santé et de la Recherche Médicale, the French Ministère de la Recherche et de la Technologie, the North Atlantic Treaty Organization, and Université Paris XII.
Present address of A. Nawrocki: Medical Academy of Bialystok, Dept. of Physiology, 15-230 Bialystok 8, Poland.
Address for reprint requests and other correspondence: F. Pecker, INSERM Unité 99, Hôpital Henri Mondor, 94010 Créteil, France (E-mail: francoise.pecker{at}im3.inserm.fr).
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.
First published January 30, 2002;10.1152/ajpcell.00471.2001
Received 4 October 2001; accepted in final form 25 January 2002.
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