© 2001 American Heart Association, Inc.
Cellular Biology |
Cytoprotection by Jun Kinase During Nitric Oxide–Induced Cardiac Myocyte Apoptosis
From the Department of Molecular and Cellular Pharmacology, University of Miami, Fla.
Correspondence to Nanette H. Bishopric, M.D., University of Miami School of Medicine, RMSB 6038, 1600 NW 10th Ave, Miami, FL 33136. E-mail nhb{at}chroma.med.miami.edu
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Abstract |
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Abstract—Nitric oxide (NO) induces apoptosis in cardiac myocytes through an oxidant-sensitive mechanism. However, additional factors appear to modulate the exact timing and rate of NO-dependent apoptosis. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) (extracellular signal–regulated kinase [ERK] 1/2, c-Jun N-terminal kinase [JNK] 1/2, and p38MAPK) in NO-mediated apoptotic signaling. The NO donor S-nitrosoglutathione (GSNO) induced caspase-dependent apoptosis in neonatal rat cardiac myocytes, preceded by a rapid (<10-minute) and significant (
50-fold)
activation of JNK1/2. Activation of JNK was cGMP dependent and was
inversely related to NO concentration; it was maximal at the lowest
dose of GSNO (10 µmol/L) and negligible at 1 mmol/L. NO slightly
increased ERK1/2 beginning at 2 hours but did not affect p38MAPK
activity. Inhibitors of ERK and p38MAPK activation did not affect cell
death rates. In contrast, expression of dominant-negative JNK1 or
MKK4 mutants significantly increased NO-induced apoptosis at 5
hours (56.77% and 57.37%, respectively, versus control, 40.5%),
whereas MEKK1, an upstream activator of JNK, sharply reduced apoptosis
in a JNK-dependent manner. Adenovirus-mediated expression of
dominant-negative JNK1 both eliminated the rapid activation of JNK by
NO and accelerated NO-mediated apoptosis by 2 hours. These data
indicate that NO activates JNK as part of a cytoprotective response,
concurrent with initiation of apoptotic signaling. Early, transient
activation of JNK serves both to delay and to reduce the total extent
of apoptosis in cardiac
myocytes.
Key Words: apoptosis • cytoprotection • Jun kinase • nitric oxide • cGMP
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Introduction |
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Inappropriate or defective apoptosis contributes to numerous degenerative and autoimmune syndromes1 and is increasingly recognized to play a role in heart diseases associated with aging, pressure overload, stretch, tachycardia, hypertrophy, and myocardial infarction (reviewed in References 22 and 3; see also References 44 –8). The molecular regulation of cardiac myocyte apoptosis is incompletely understood but is likely to involve both tissue-specific and general mechanisms.9 10
The free radical gas nitric oxide (NO) is synthesized from L-arginine by at least 3 isoforms of NO synthase, all of which are expressed in the heart.11 12 We have previously shown that induction of apoptosis by inflammatory cytokines requires NO production and that exposure to an NO donor directly induces cardiac myocyte apoptosis in a dose-dependent and antioxidant-sensitive manner.10 However, the precise role of NO remains controversial, because NO has also been reported to be antiapoptotic in cardiac myocytes under some conditions,13 14 as well as in other cell types.15 The molecular mechanisms of both NO-mediated apoptosis and cytoprotection remain poorly understood.
The mitogen-activated protein kinase (MAPK) family, including extracellular signal–regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases 1 and 2 (JNK1/2), and p38MAP kinases (p38MAPK), plays an important role in survival signaling in many cell types, including cardiac myocytes.16 17 18 19 20 21 However, NO has not previously been shown to signal through MAPK effectors in cardiac myocytes, and it is unknown whether these kinases contribute to NO-dependent cell fate decisions. In this study, we report that the physiological NO donor S-nitrosoglutathione (GSNO) simultaneously induces caspase-dependent apoptosis and JNK activation. Remarkably, however, we find that activation of JNK blunts NO-induced apoptosis. We show, using plasmid- and adenovirus-mediated transfection of specific JNK pathway mutants, that JNK activation is directly protective against NO-mediated apoptosis and that JNK inhibition both exacerbates and accelerates cell death induced by NO. We conclude that early activation of JNK is an important cytoprotective response to NO in the cardiac myocyte and serves to attenuate a parallel NO-mediated, caspase-dependent cell death pathway.
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Materials and Methods |
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Materials
Plasmids containing dominant-negative mutants of JNK1 (JNKK1/SEK1/MKK4) and a constitutively active mutant of MEKK1 (JNK/SAPK [APF], JNKK/SEK-1 [K116] and MEKKCOOH, respectively)22 were the kind gift of Dr Gary L. Johnson (National Jewish Center for Immunology and Respiratory Medicine, Denver, Colo). Construction of the recombinant adenovirus expressing the dominant-negative JNK(APF) construct (dnJNK) will be described elsewhere (C. Dougherty et al, unpublished data, 2001). Dr Shawn Black (Merck-Frosst, Quebec, Canada) generously provided the polyclonal antibody to activated caspase-3. The poly(ADP-ribose) polymerase (pADPRp) antibody was supplied by Dr Guy Poirier (Health and Environment Unit, Hospital Research Center of University of Laval, Quebec, Canada). Anti–sarcomeric myosin antibody (MF-20) was obtained from the Developmental Studies Hybridoma Bank at the University of Iowa (Ames, Iowa). Hoechst 33342, propidium iodide (PI), and KT5823 were purchased from Calbiochem-Novabiochem Corp. PD98059 was purchased from New England BioLabs. Caspase inhibitor zVAD-fmk was from Enzyme System Products. All other reagents were purchased from Sigma Chemical Co except as noted.
Immunohistochemical Analysis
Myocytes were plated on 2-well coverslip dishes
(Nalge Nunc International) at a density of
4x105/cm2 and
cultured for at least 5 days before use as previously
described.10 23
Cells were treated with various amounts of GSNO (10, 100, and 500
µmol/L) for 5 hours, fixed, and permeabilized with ice-cold methanol.
Slides were next blocked with 5% horse serum/PBS and sequentially
incubated with anti–caspase-3 polyclonal antibody (1:2000), horse
anti-rabbit IgG antibody conjugated to biotin (3 µg/mL, Vector
Laboratories), and FITC-avidin (5 µg/mL, Vector Laboratories). The
slides were then mounted, imaged, and digitally recorded on a laser
scanning confocal microscope (Multiprobe 2001, Molecular
Dynamics).
Cell Transfection and Infection
Cells were transfected with 1 µg of total DNA plus
1 µg of lipofectamine (GeneFECTOR) per chamber, using plasmids
containing dominant-negative mutants of JNK1, MKK4, constitutively
active MEKK1, or a blank pcDNA3 vector (Invitrogen). These
plasmids were cotransfected with a muscle-specific human
skeletal actin promoter driving green fluorescent protein (GFP)
expression at a ratio of 1:100 GFP:kinase expression vector.
Forty-eight hours after transfection, the cells were treated with 1
mmol/L GSNO for 5 hours. After vital staining with the fluorescent DNA
binding dyes Hoechst 33342 and PI, cell images were recorded using a
laser scanning confocal microscope (Multiprobe 2001, Molecular
Dynamics). Cardiac myocytes were identified by GFP
fluorescence.
Adenovirus infection was performed as previously described.24 Briefly, cardiac myocytes on 2-well coverslip slides were infected with 20 plaque-forming units per cell of dnJNK1-GFP adenovirus, whereas control cells were infected with 20 plaque-forming units per cell of Adß-galactosidase–(ßgal) GFP. Forty-eight hours after infection, the cells were treated with 1 mmol/L GSNO for 5 hours. Infection efficiency was monitored by GFP expression. Staining and imaging was performed as described above.
Cardiac Myocyte Cell Culture and Analyses
of Apoptosis
Culture of cardiac
myocytes,8 10 23
analysis of DNA
fragmentation,10 pADPRp
cleavage assay,10 and
protein kinase assays17 were
conducted exactly as previously
described.
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Results |
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Morphological and DNA Fragmentation Study of GSNO-Induced Apoptosis
During apoptosis, DNA is cleaved into nucleosomal fragments ("laddering") by caspase-3–dependent activation of a specific DNase.25 We observed extensive fragmentation of myocyte DNA 5 hours after treatment with GSNO (10 µmol/L to 1 mmol/L); the extent of DNA laddering was positively dose dependent and maximal at 1 mmol/L GSNO (Figure 1A
, lanes 1 through 4). GSNO-induced DNA
fragmentation was abolished by 30-minute pretreatment with the caspase
inhibitor zVAD-fmk (50 µmol/L)
(Figure 1A, lane 5). Quantification of apoptotic cardiac
myocytes under the same conditions confirmed that apoptosis was
directly proportional to GSNO concentration and was maximal at 1 mmol/L
(42.5% ±1.18 in apoptotic versus 7.1±0.81 in vehicle-treated cells,
P<0.01).
(Figure 1B). Necrosis was not induced by GSNO at these
concentrations (data not shown).
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500 cells). Values are percentage apoptotic cells±SEM. *P<0.05, **P<0.01 for comparison with control cells. Necrotic nuclei represented <1% of the total in each case. C, Activation of pADPRp cleavage by an NO donor. Proteolytic cleavage of pADPRp was analyzed after 5 hours of treatment with indicated concentrations of GSNO in the absence or presence of zVAD-fmk (50 µmol/L). C indicates control; zVAD, zVAD-fmk. Top, Representative gel. Bottom, Quantification of 3 pADPRp assays. Data are mean±SEM increase in 85-kDa cleavage product (shaded bars) normalized to control (n=3). *P<0.05, **P<0.01 for comparison with untreated cells, §P<0.01 vs ZVAD+GSNO–treated cells. Open bars indicate uncleaved pADPRp. D, NO activates caspase-3 in cardiac myocytes. Cardiac myocytes were treated for 5 hours with indicated concentrations of GSNO and imaged with an antibody against the active form of caspase-3 (courtesy of Dr S. Black). Shown are representative images from 2 separate experiments.
Caspase-3 Activation by NO
As illustrated in
Figure 1A
, zVAD-sensitive DNA cleavage provides strong
evidence for the activation of effector caspases such as caspase-3. To
confirm that effector caspases are activated by NO in cardiac myocytes,
we looked for NO-dependent cleavage of the caspase-3 substrate
pADPRp.26 As expected,
exposure to GSNO induced the cleavage of pADPRp in a dose-dependent
manner, and appearance of the 85-kDa pADPRp cleavage product was
blocked by the caspase inhibitor zVAD-fmk (50 µmol/L).
To demonstrate the specific activation of caspase-3, we used
immunofluorescent staining with an antibody against the active form of
this enzyme.
Figure 1D contains representative images of cardiac myocytes
after 5 hours of treatment with vehicle or GSNO. Specific fluorescence
was maximal in the cells treated with 500 µmol/L GSNO and similar to
control levels in the cells exposed to 10 µmol/L GSNO. These findings
are consistent with dose-dependent NO activation of caspase-3 in
cardiac myocytes.
Activation of JNK by NO Is Negatively Dose
Dependent and Mediated by cGMP
Exposure of cardiac myocytes to GSNO for 1 hour
resulted in a 50-fold induction of JNK activity
(Figure 2A), as measured by a substrate affinity
binding assay. Unexpectedly, JNK activation by NO was negatively dose
dependent; JNK activation peaked at 10 µmol/L GSNO and was minimal at
1 mmol/L. NO-dependent JNK activation and induction of apoptosis were
thus inversely related
(Figure 2B).
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A major effector of NO signal transduction is the guanylate
cyclase/cGMP pathway. We used the cell-permeant cGMP analogue,
8-bromo-cGMP (8-Br-cGMP), and KT5823, a selective inhibitor of protein
kinase G (cGK)
(Figure 2C), to investigate this mechanism. Treatment with
either 8-Br-cGMP (100 µmol/L) or GSNO (10 µmol/L) caused a
significant induction in JNK activity at 1 hour. The combination of
8-Br-cGMP and GSNO produced a significantly greater activation of JNK
than either reagent alone, which suggests a cooperative effect.
Activation of JNK by GSNO was eliminated by pretreatment with the cGK
inhibitor KT5823 (1 µmol/L). Cotreatment with the antioxidant
N-acetylcysteine or with the
pro-oxidant buthionine-[S,R]-sulfoximine (BSO) did not
significantly affect JNK induction by GSNO (data not shown). These data
are consistent with a primary role for cGMP-dependent effectors in
modulating the induction of JNK by NO.
Asynchronous Activation of ERK and JNK by
NO
ERK activation was determined in a direct kinase
activity assay using myelin basic protein as substrate. Induction of
ERK was 2.4-fold of control at 10 µmol/L GSNO concentration and did
not change further significantly at up to 1 mmol/L
(Figure 3A). In the same lysates, activity of p38 did not
change significantly by addition of GSNO
(Figure 3B).
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In subsequent time course experiments, activation of
JNK occurred within 10 minutes, peaked at 1 hour, and was sustained for
at least 4 hours, returning to control levels by 6 hours
(Figure 4). In contrast, GSNO activation of ERK was biphasic,
with a small initial peak at 30 minutes and a larger sustained
elevation between 2 and 24 hours. p38MAPK activity did not change over
the course of the 24 hours
(Figure 4).
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), ERK1/2 (
), and p38MAPK (
). Top, Representative autoradiograms. Bottom, Mean data from 3 experiments. Values are mean±SEM. *P<0.05, **P<0.01.
Cytoprotective Effect of JNK1 in NO-Induced
Cardiac Myocyte Apoptosis
The functional relevance of MAPK activation was tested
using the MEK1 inhibitor PD98059 (50 µmol/L) or the p38MAPK inhibitor
SB203580 (5 µmol/L) to inhibit ERK and p38MAPK activation,
respectively. Neither of these agents inhibited or enhanced the
development of GSNO-induced cardiac myocyte apoptosis
(Figure 5 and data not shown).
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To explore the role of JNK, we examined the effects of
previously characterized dominant-negative and constitutively active
mutants of proteins in the JNK pathway on GSNO-induced
apoptosis.27 Transfection of
either dominant-negative JNK or MKK4 significantly increased apoptosis
rates in GSNO-treated myocytes (control, 40.5±2.1%; dnJNK,
56.77±5.32%; dnMKK4, 57.37±3.09%,
P<0.01)
(Figure 6). Basal apoptosis rates were also increased
slightly by both dnJNK and dnMKK4
(Figure 6). Conversely, a constitutively active MEKK1 mutant
significantly reduced apoptosis in cells exposed to GSNO (MEKK1,
19.79±4.8%, P<0.01).
Although MEKK1 has been reported to activate ERK in some systems, MEKK1
was able to inhibit apoptosis in the presence of either PD98059 or
SB203580, demonstrating that this protective effect was not mediated by
downstream activation of either ERK or p38MAPKs. In contrast,
coexpression of dnJNK completely neutralized the antiapoptotic effects
of MEKK1, indicating that JNK activation is essential to this
effect.
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Inhibition of JNK1 Accelerates
NO-Mediated Apoptosis
The effect of JNK on the timing of NO-mediated
apoptosis was then determined in cardiac myocytes with and without
adenovirus-mediated expression of ßgal or dnJNK. In initial
experiments, we confirmed that adenovirus-mediated expression of dnJNK
both eliminated NO-mediated activation of JNK and significantly
increased NO-induced apoptosis as determined by morphological criteria
(43.2±2.75 for Adßgal, versus 62±2.58 for dnJNK1,
P<0.01;
Figure 7). As shown previously, the timing of DNA
fragmentation in response to a single dose of 1 mmol/L GSNO was highly
predictable, beginning at 4 hours and ending at 8 hours, in both
uninfected and Adßgal-infected myocytes
(Figure 8). However, in the presence of dnJNK, DNA cleavage
reproducibly developed within 2 hours and was complete by 5 hours after
GSNO treatment, indicating an acceleration of the entire process. The
difference in timing (2 hours) could not be attributed to
differences in basal apoptotic rates among the different treatment
groups
(Figure 8) and was confirmed by direct scoring of apoptotic
myocytes at time points from 1 to 5 hours (data not shown). We conclude
that preventing the NO-mediated, early activation of JNK accelerates
the onset of NO-induced DNA
fragmentation.
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Discussion |
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The data presented here strongly indicate that early JNK activation is part of an endogenous cardiac myocyte defense strategy against concentrations of NO attainable in vivo.28 Like other antiapoptotic strategies, this activation serves as much to delay as to moderate NO-dependent cytotoxic stress, perhaps to allow for limited bursts of NO production occurring under physiological conditions. We recently proposed a similar role for NO-dependent induction of the antiapoptotic protein Bcl-x(L).10
Our studies demonstrate that JNK activation cannot be causative in the apoptotic response to NO. First, NO-induced apoptosis and JNK activation can be separately inhibited. Although NO requires oxygen free radical availability to induce apoptosis,10 JNK activation was unaffected by pro- or antioxidant thiol reagents N-acetylcysteine and BSO (data not shown). Unlike NO-dependent apoptosis, JNK activation was blocked by a protein kinase G inhibitor. Moreover, NO activated JNK and apoptosis with opposite dose dependence. NO thus induces 2 functionally antagonistic effects through distinct intracellular pathways, as follows: an early wave of JNK activation, mediated by cGK and maximal at low NO concentrations, and a later phase of oxidant-induced DNA laddering that is most prominent at high NO doses.
Our data indicate that JNK activation, rather than promoting NO-mediated apoptosis, in fact is cytoprotective. JNK is activated by a variety of stresses that induce cardiac cell death, including mechanical stress,29 cytokines,30 and oxidizing agents17 ; however, JNK has also been shown to transmit cardiac myocyte growth signals.21 31 It is important to note that a cause-and-effect relationship between JNK and apoptosis has not yet been established in the cardiac myocyte, and most of the direct evidence associating JNK with apoptotic signaling is derived from other cell types.16 22 32 33 Even if JNK is required for apoptosis in some systems, it is not clear whether JNK is universally proapoptotic. JNK promotes cell growth and proliferation in many tumor cell lines and is required for oncogenic transformation by Ras and Bcr/abl.34 Importantly, stress activation of JNK appears to be cytoprotective in some cases. Upstream inhibition of JNK and p38 at the level of MKK4/6 potentiated tumor necrosis factor (TNF)–induced apoptosis, whereas activation had the opposite effect35 ; MKK4 inhibition sensitized HeLa cells to apoptosis induced by photodynamic therapy.36 It seems likely that the effects of JNK are determined in part by the activity of other signal-transduction pathways as well as cell-specific factors.
In our experiments, the cytoprotective effects of JNK were independent of p38 and ERK activity. In a macrophage cell line, JNK activation by NO was also shown to be cytoprotective but only in the presence of activated p38.37 In cardiac myocytes, forced activation of JNK induced hypertrophy, but coactivation of p38 and JNK promoted apoptosis.21 A limitation of many studies in this field is the absence of specific JNK inhibitors and the resulting need to characterize JNK function through transfection of dominant-negative and constitutively active upstream JNK mutants. The role of timing must also be considered in this context; whether JNK is interpreted as a survival signal may depend on whether its activation is transient rather than sustained. The short-lived induction of JNK by NO clearly represents such a transient stimulus.
A recent study by Minamino et
al38 demonstrated that MEKK1
protects against
H2O2-induced apoptosis in
embryonic stem cell–derived cardiac myocytes, apparently
through JNK-dependent inhibition of TNF-
signaling. We likewise
observed that inhibition of JNK increased cardiac myocyte production of
TNF (data not shown). However, we were unable to demonstrate
that TNF- induced apoptosis either by itself or in the context of NO
exposure (Reference 1010 and data not shown). Taken together, these
findings indicate that JNK can exert cytoprotective effects through
more than one mechanism in cardiac myocytes.
NO can activate either cytoprotective or cytotoxic mechanisms, depending on the cell type.15 37 39 40 41 42 43 However, both apoptotic and cytoprotective roles have been ascribed to NO in cardiac myocytes.10 13 14 44 45 46 47 Resolving this seeming contradiction requires a clearer understanding of the cellular targets of NO. We demonstrate here that NO induces apoptosis through activation of caspase-3, as reflected in cleavage of caspase-3 substrate pADPRp, internucleosomal cleavage of DNA (implying activation of caspase-dependent DNases25 ), appearance of an activated caspase-3 antigen, and zVAD-fmk–sensitive cell death. Thus, although NO has been reported to inactivate caspase-3 in vitro through stable nitrosylation of its active site,48 other factors within the cell determine the actual targets of NO.
Collectively, our findings show the importance of both timing and concentration in modulating the effects of NO. The observed lack of impact of ERK on myocyte survival may be partly attributable to its delayed activation. The negative relationship between NO concentration and JNK activation may explain why the burst of NO formed during cytokine exposure is strongly proapoptotic, whereas lower levels of NO production may remain below this threshold and act as a cytoprotectant. Additional work will be required to identify the specific conditions and targets that govern NO- and JNK-mediated cell fate decisions under physiological conditions.
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Acknowledgments |
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This work was supported by an Established Investigator Grant from the American Heart Association (to N.H.B.) and by grants from the Miami Heart Research Institute (to N.H.B.) and the NIH (Grant HL44578, to K.A.W.). P.A. is the recipient of a postdoctoral fellowship from the American Heart Association (Florida/Puerto Rico Affiliate) and of awards from the George Soros Foundation and the government of Hungary. We gratefully acknowledge Daryl Discher for technical and administrative support and the University of Miami Confocal Microscope Facility for assistance with cell imaging.
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Footnotes |
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Original received August 22, 2000; revision received January 10, 2001; accepted January 10, 2001.
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