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(Circulation. 1999;99:1685-1691.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Inhibition of p38 Mitogen-Activated Protein Kinase Decreases Cardiomyocyte Apoptosis and Improves Cardiac Function After Myocardial Ischemia and Reperfusion
From the Division of Emergency Medicine (X.L.M., F.G., B.L.L., T.A.C.), Thomas Jefferson University, Philadelphia, and the Departments of Bone and Cartilage (S.K., J.C.L.), Experimental Toxicology (C.S.L.), and Cardiovascular Pharmacology (C.W., G.Z.F., T.-L.Y.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
Correspondence to Xin L. Ma, MD, PhD, Division of Emergency Medicine, Jefferson Medical College, 1020 Sansom St, Philadelphia, PA 19107. E-mail ma1{at}jeflin.tju.edu
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Abstract |
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Background—Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in apoptotic cell death. The role of p38 MAPK in myocardial injury caused by ischemia/reperfusion, an extreme stress to the heart, is unknown.
Methods and Results—Studies were performed with isolated, Langendorff-perfused rabbit hearts. Ischemia alone caused a moderate but transient increase in p38 MAPK activity (3.5-fold increase, P<0.05 versus basal). Ischemia followed by reperfusion further activated p38 MAPK, and the maximal level of activation (6.3-fold, P<0.01) was reached 10 minutes after reperfusion. Administration of SB 203580, a p38 MAPK inhibitor, decreased myocardial apoptosis (14.7±3.2% versus 30.6±3.5% in vehicle, P<0.01) and improved postischemic cardiac function. The cardioprotective effects of SB 203580 were closely related to its inhibition of p38 MAPK. Administering SB 203580 before ischemia and during reperfusion completely inhibited p38 MAPK activation and exerted the most cardioprotective effects. In contrast, administering SB 203580 10 minutes after reperfusion (a time point when maximal MAPK activation had already been achieved) failed to convey significant cardioprotection. Moreover, inhibition of p38 MAPK attenuated myocardial necrosis after a prolonged reperfusion.
Conclusions—These results demonstrate that p38 MAPK plays a pivotal role in the signal transduction pathway mediating postischemic myocardial apoptosis and that inhibiting p38 MAPK may attenuate reperfusion injury.
Key Words: reperfusion • signal transduction • apoptosis • contractality • myocardial infarction
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Introduction |
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Growing evidence from both animal experiments and clinical observations indicates that apoptosis, a form of cell death that is distinct from necrosis, plays a key role in myocardial reperfusion injury.1 2 3 4 5 The signal transduction pathway that leads to this postischemic myocardial apoptosis, however, remains largely unexplored. Recent cell biology studies have demonstrated that c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (SAPKs) and p38 mitogen-activated protein kinase (MAPK), 2 members of the MAPK family, are activated by a variety of cellular stresses6 7 and that their activation results in apoptosis and cell death.8 9 10 11 12 13 14 It has also been demonstrated recently that myocardial ischemia/reperfusion, an extreme pathological stress to the heart, activates p38 MAPK.15 16 17 However, whether activation of p38 MAPK plays an important role in postischemic myocardial apoptosis has not been determined.
Given that apoptosis is an active, gene-directed process, inhibition of apoptosis could be achieved more successfully than prevention of necrosis, a passive form of cell death that is inflicted by the acute stimulus.18 However, it is well recognized that apoptosis proceeds through a genetically programmed series of biochemical and morphological steps designed to avoid the indiscriminate release of cytosolic contents and the ensuing inflammatory response; removal of damaged myocytes through apoptosis may be a mechanism by which the heart limits the extent of the potentially more destructive process of necrosis.19 Thus, there exists a need for further clarification as to whether or not inhibition of myocyte apoptosis might result in improved recovery of left ventricular function after myocardial ischemia and reperfusion.
The objectives of the present studies were to (1) determine the time course of p38 MAPK activation in isolated, perfused rabbit hearts subjected to ischemia and reperfusion in a quantitative manner; (2) establish a direct link between p38 MAPK activation and myocyte apoptosis after myocardial ischemia and reperfusion; and (3) define the effects of inhibition of p38 MAPK activation and ischemia-induced apoptosis by specific pharmacological agents on functional damage in the rabbit heart.
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Methods |
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Experimental Preparation
Rabbits were anesthetized with sodium pentobarbital (35 mg/kg IV) and heparinized with sodium heparin (1000 U/kg IV). Five minutes after heparin injection, a midsternal thoracotomy was performed, and the heart was rapidly excised and placed into ice-cold Krebs-Henseleit (KH) buffer solution consisting of (in mmol/L) NaCl 118, KCl 4.75, KH2PO4 1.19, MgSO4 · 7H2O 1.19, CaCl2 · 2H2O 2.54, NaHCO3 25, EDTA 0.5, and glucose 11. Within 30 seconds, the heart was mounted onto a Langendorff heart perfusion apparatus (Radnoti Glass Technology, Inc). The hearts were perfused in a retrograde fashion via the aorta at a constant pressure of 60 mm Hg with oxygenated KH solution in an atmosphere of 95% O2 and 5% CO2 at 37°C. Coronary flow (CF) was measured via an in-line flow probe connected to an ultrasonic flowmeter (Transonic Systems Inc). The experiments were performed in adherence with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals and were approved by the Thomas Jefferson University Committee on Animal Care.
Experimental Protocol
After a 15-minute equilibration time, hearts were subjected to
complete global ischemia (MI) for 30 minutes (unless otherwise
indicated) by turning off the perfusion system. After 30 minutes of
ischemia the perfusion system was restarted, and the hearts
were reperfused (R) for 0 to 60 minutes (for studying the time course
of p38 MAPK activation, formation of apoptosis, and cardiac
function) or 120 minutes (for myocardial necrosis). Hearts were
randomly divided into 4 major treatment groups. In the first group,
hearts were subjected to MI/R but received vehicle only (0.9% NaCl,
MI+vehicle). The second group of hearts was treated with SB 203580 (a
pyridinyl imidazole inhibitor of p38 MAPK; final
concentration, 1 or 10 µmol/L) before ischemia (for 10
minutes) and during the entire period of reperfusion (MI+SB/IR). In the
third group of hearts, treatment with SB 203580 (10 µmol/L) was
initiated at the onset of reperfusion and continued for the rest of the
reperfusion period (MI+SB/R). In the fourth group of hearts, SB 203580
(10 µmol/L) treatment was delayed, beginning 10 minutes after
reperfusion was initiated and continuing for the rest of the
reperfusion period (MI+SB/DT). Drugs were infused into the heart via a
side arm in the perfusion line located just proximal to the heart
cannula. The rate of infusion (1/1000 of CF) was adjusted on the basis
of the CF rate so that the desired final concentration was obtained.
Sham I/R hearts were continuously perfused with KH solution for 2.5
hours.
SAPK, p38 MAPK, and MAPK-Activated Protenine Kinase 2
(MAPKAP K2) Kinase Assay
At the completion of the perfusion protocol, the hearts were
frozen in LN2 and used within 1 week. The hearts
were "freeze-clamped" by using precooled aluminum tongs and
pulverized under LN2.20 The powder
was resuspended in ice-cold lysis buffer, and the protein content in
the detergent-soluble supernatant fraction was measured as described
previously.7 SAPK, p38 MAPK, and MAPKAP K2 kinases were
immunoprecipitated with antibodies specific for JNK1 and JNK2 (Santa
Cruz), p38 MAPK (SmithKline Beecham), or MAPKAP K2 (Dr J. Landry,
University of Quebec, Montreal) and assayed by using
glutathione-S-transferase–c-Jun(1–81),
glutathione-S-transferase–activating transcription
factor-2, or heat shock protein 27 as the substrate,
respectively, as described in our previous
studies.20 21 22
DNA Fragmentation (DNA Ladder)
The frozen hearts (stored at -70°C) were minced while being
thawed in lysis buffer (50 mmol/L Tris-HCl, pH 8.0; 20 mmol/L
EDTA; and 1% SDS) on ice, and proteinase K (100 µg/mL) was then
added. After incubation at 55°C with shaking for 18 hours, DNA was
extracted with phenol/chloroform 3 times, precipitated in ethanol,
treated with DNA-free RNase, reextracted, and precipitated again. Five
micrograms of DNA was then loaded onto a 1.8% agarose gel, and DNA
ladder formation was detected as described in our previous
study.20
Terminal Deoxynucleotidyl Transferase–Mediated
dUTP-Biotin In Situ Nick-End Labeling (TUNEL)
The TUNEL assay was performed using ApopTag (Oncor) according to
the manufacturer's instructions.20 Cardiomyocytes from at
least 4 slides per block that were randomly selected were evaluated
immunohistochemically to determine the number and percentage of cells
exhibiting positive staining for apoptosis. For each slide 10
fields were randomly chosen, and by using a defined rectangular field
area (x20 objective), a total of 100 cells per field were counted. The
index of apoptosis was determined (ie, number of
apoptotic myocytes divided by the total number of myocytes
counted x100) from a total of 40 fields per heart, and the assays were
performed in a blinded manner.
Assessment of Myocardial Contractile Function
Cardiac contractile function was assessed as described
previously.23 In brief, a latex balloon was inserted into
the left ventricular cavity and connected to a pressure
transducer. The balloon was initially inflated with water to produce an
end-diastolic pressure of 8 to 10 mm Hg. Left
ventricular pressure was continually recorded on a
Power Macintosh computer via a data acquisition system (MacLab, AD
Instruments, Inc). The left ventricular systolic
pressure, left ventricular diastolic pressure,
left ventricular generated pressure (LVGP; systolic
minus diastolic), the maximal value of the first derivative
of left ventricular pressure
(dP/dtmax), heart rate, the pressure-rate
product (PRP; heart rate times generated pressure), and CF were
automatically analyzed.
Determination of Myocardial Necrotic Injury
Myocardial necrotic injury was assessed by measuring myocardial
creatine kinase (CK) loss and nitro blue tetrazolium (NBT) staining as
previously reported.24 In brief, 
100 mg myocardial
tissue was taken at the end of each experiment and
homogenized in cold 0.25 mol/L sucrose (1:10, wt/vol)
containing 1 mmol/L EDTA and 0.1 mmol/L mercaptoethanol.
Homogenates were centrifuged and the supernatant
was decanted. CK activity was analyzed using a Beckman DU 640
spectrophotometer as reported previously.24 Protein
concentration was determined by the bicinchoninic acid method
(Pierce). CK loss was calculated by subtracting CK activity of MI/R
hearts from the CK activity of sham ischemic hearts and
expressed in IU per 100 mg protein. The remainder of the heart tissue
was cut into slices 2 mm thick. Slices were incubated in 0.1%
NBT in phosphate buffer at pH 7.4 and 37°C for 15 minutes. The
unstained portion (which is the irreversibly injured, necrotic region)
was then separated from the stained (nonnecrotic) portion. Both
sections were weighed, and the results were expressed as a percentage
of necrotic tissue over total ventricular mass.
Statistical Analysis
All values in the text, tables, and figures are
presented as mean±SEM of n independent experiments. All data
were subjected to ANOVA followed by the Bonferroni correction for post
hoc t tests. Probabilities of P
0.05 were
considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Time Course of p38 MAPK Activation by Ischemia and Ischemia/Reperfusion and Its Inhibition by SB 203580
To determine the time course of p38 MAPK activation by ischemia and reperfusion, the hearts were subjected to 0 (control), 15, 30, 40, 50, 60, or 90 minutes of ischemia alone or 30 minutes of ischemia followed by 10, 20, 30, or 60 minutes of reperfusion (at least 5 hearts per time point). Ischemia alone caused a modest (3- to 4-fold), transient (peaked at 15 minutes, declined at 30 minutes of ischemia, and maintained at low levels thereafter) increase in p38 MAPK activity (Figure 1
). However, when myocardial tissue was
reperfused after 30 minutes of ischemia, p38 MAPK was markedly
reactivated. A 6.3-fold increase in p38 MAPK activity was
observed at 10 minutes after reperfusion and remained significantly
elevated at 20 minutes throughout reperfusion. At 30 and 60 minutes of
reperfusion, p38 MAPK activity returned to a level that was not
significantly different from control (Figure 1). Administration
of 1 µmol/L SB 203580, a specific p38 MAPK
inhibitor, only slightly reduced p38 MAPK activity (maximal
activity at 10 minutes of reperfusion: 5.8±0.95-fold increase in
1 µmol/L SB 203580–treated hearts versus 6.3±0.83-fold
increase in vehicle-treated hearts, P>0.05). In contrast,
when 10 µmol/L SB 203580 was administered, p38 MAPK activity was
markedly inhibited (1.26±0.62-fold increase, P<0.001
versus vehicle-treated hearts, P>0.05 versus sham MI/R
hearts; Figure 2).
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). Each point in top panel represents mean±SE of at
least 5 animals. *P<0.05, **P<0.01 vs
time zero. Bottom panels are representative
autoradiograms of ischemia with reperfusion or
ischemia alone.
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Detection of DNA Fragmentation (DNA Ladder) in
Ischemic/Reperfused Hearts and Its Inhibition by the p38
MAPK Inhibitor
In myocardial tissue from sham ischemic hearts, no DNA
ladder was detected (Figure 3, lanes 1
and 7). In contrast, the formation of DNA nucleosome ladders was
clearly detected in myocardial tissues obtained from all 5 I/R hearts
receiving vehicle only (Figure 3, lanes 2 through 6). In the 5
rabbit hearts treated with 10 µmol/L SB 203580, DNA ladder
formation was absents in 3 heart samples and significantly reduced in
the other 2 (Figure 3, lanes 8 through 12).
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In Situ Determination of Apoptotic Myocytes in
Ischemic/Reperfused Rabbit Hearts and Its Inhibition by SB
203580
Consistent with the absence of DNA ladders, few myocytes
stained positive in tissue from sham ischemic hearts (Figures 4A and 5).
In contrast, TUNEL-positive nuclei were prevalent in tissues from I/R
hearts receiving vehicle only (Figures 4B and 5). Most
notably, SB 203580 treatment markedly reduced the numbers of myocytes
that were stained positive by TUNEL (Figures 4C and 5).
Therefore, after 30 minutes of ischemia and 60 minutes of
reperfusion, TUNEL-positive myocytes were reduced to 14.7±3.2% in SB
203580–treated hearts compared with 30.6±3.5% in vehicle-treated
hearts (P<0.01, Figure 5).
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Effect of SB 203580 on Myocardial Necrotic Injury After
Ischemia/Reperfusion
As summarized in the
Table, 30 minutes of global
ischemia and 120 minutes of reperfusion resulted in significant
necrotic injury, as evidenced by a large area of negative NBT staining
and significant CK loss. Administration of 1 µmol/L SB 203580
had no significant effects on either myocardial CK loss or the size of
negative NBT staining. However, when 10 µmol/L SB 203580 was
administered 10 minutes before ischemia and during reperfusion,
a significant reduction in both myocardial CK loss and size of negative
NBT staining was observed (Table 1).
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Effect of Inhibition of p38 MAPK on Cardiac Function Recovery:
Dose-Protection Relationship
Global ischemia decreased CF to zero, and functional
myocardial contraction was completely absent 30 minutes after
ischemia. When perfusion was restored, functional contraction
usually resumed within 5 minutes. CF, LVGP,
dP/dtmax, and PRP all gradually recovered and
reached a maximal level 20 to 40 minutes after reperfusion. In
vehicle-treated hearts, LVGP and PRP declined again 60 minutes after
reperfusion while CF and dP/dtmax remained at a
relatively stable level. Treatment with 1 µmol/L SB 203580
slightly increased LVGP 40 minutes after reperfusion and enhanced
dP/dtmax 40 and 60 minutes after reperfusion.
However, none of these differences were statistically significant. In
contrast, when 10 µmol/L SB 203580 was administered, a
significant improvement in cardiac contractile function was observed.
At 60 minutes of reperfusion, LVGP, dP/dtmax, and
PRP were significantly higher compared with vehicle-treated hearts
(P<0.001 for LVGP and dP/dtmax and
P<0.05 for PRP). Moreover, although SB 203580 exerted no
direct vasorelaxation effects in control hearts or MI/R hearts when
infused up to 30 µmol/L for 1 minute (data not shown), treatment
with 10 µmol/L SB 203580 before ischemia and during
reperfusion significantly improved CF 60 minutes after reperfusion
(P<0.05, Figure 6).
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Time-Dependent Inhibition of p38 MAPK on Cardiac Function
Recovery
Previous experiments by other investigators as well as our own
data have demonstrated that transient p38 MAPK activation can be
detected after 10 to 20 minutes of ischemia without
reperfusion. However, the influence of this ischemia
activated p38 MAPK on myocardial injury after reperfusion
remains unknown. Moreover, our time course study has shown that maximal
p38 MAPK activity was observed 10 minutes after reperfusion and
declined thereafter. It was not clear whether this peak increase of p38
MAPK in early reperfusion played a key role in subsequent myocardial
injury. To address this issue, 2 additional experiments were performed.
In the first experiment, SB 203580 (10 µmol/L, a concentration
that exerted significant protective effects when given both before
ischemia and after reperfusion), was given during reperfusion
only (MI+SB/R). As illustrated in Figures 7 and 8,
administration of SB 203580 during reperfusion only markedly improved
myocardial function recovery and significantly reduced myocardial
necrotic injury, as evidenced by a reduction in necrotic area and a
decrease in myocardial CK loss. In the second experiment,
administration of SB 203580 was delayed until 10 minutes after
reperfusion, a time point at which maximal p38 MAPK activation had
already occurred. No significant protective effects were observed
(Figures 7 and 8A). Taken together, these 2 experiments
suggest that the peak increase in p38 MAPK activation soon after
reperfusion is a critical early event that plays an important role in
the determination of the final extent of myocardial reperfusion
injury.
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To provide further evidence that the cardioprotective effects of
SB 203580 described above were directly related to its inhibition of
p38 MAPK, activation of MAPKAP kinase 2 (MAPKAP K2), a specific
downstream target of p38 MAPK, was measured in the myocardial tissues
from the 5 experimental groups. In sham ischemic tissue, no
MAPKAP K2 activity was detected (Figure 8B
, lane 1). However,
MAPKAP K2 activity was markedly enhanced in myocardial tissues from the
hearts subjected to 30 minutes of ischemia and 10 minutes of
reperfusion (Figure 8B, lane 2). Treatment with SB 203580 both
before ischemia and reperfusion completely blocked the
activation of MAPKAP K2 (Figure 8B, lane 3). Administration of
SB 203580 during reperfusion only also markedly inhibited MAPKAP K2
activity (Figure 8B, lane 4). In contrast, when treatment with
SB 203580 was delayed until 10 minutes after reperfusion (100 mg
myocardial tissue from the left ventricular free wall was
taken 10 minutes after reperfusion but before initiating SB 203580
infusion), MAPKAP K2 activity was comparable to that observed in
vehicle-treated hearts (Figure 8B, lane 5).
To investigate whether or not SB 203580 treatment also inhibited SAPK
activity, thereby exerting cardiovascular protection,
we determined the time course of SAPK activation in the presence and
absence of 10 µmol/L SB 203580. Consistent with our
previous report,20 SAPK activity was markedly elevated
after reperfusion; peak activation occurred 20 minutes after
reperfusion (Figure 9, open circles and
representative autoradiogram A).
Treatment with SB 203580 had no effect on SAPK activity at any time
point observed (Figure 8C, lanes 2 and 3 and Figure 9, filled circles and representative
autoradiogram B). This result suggests that the
cardiovascular protection observed with SB 203580
treatment was not related to SAPK activation.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present studies provide crucial information in clarifying the role of stress-response MAPK in response to ischemic injury. Our results demonstrated that ischemia alone resulted in a transient, moderate (3.5-fold) increase in p38 MAPK activation. On reperfusion, however, marked activation of p38 MAPK was observed, with a 6.3-fold activation achieved
10 minutes after reperfusion. These
results demonstrate for the first time in a quantitative manner that,
although ischemia alone can activate p38 MAPK,
ischemia followed by reperfusion results in a more profound p38
MAPK activation. These results also lead us to hypothesize that the
strong activation of p38 MAPK by reperfusion may play a more
significant role in subsequent myocardial injury than previously
realized. A novel finding in our study is that administration of a p38 MAPK inhibitor, SB 203580, markedly reduced postischemic myocardial apoptosis. Although previous studies have demonstrated that p38 MAPK plays a key role in apoptosis in a variety of cell culture systems8 9 10 11 12 13 14 25 and that ischemia/reperfusion activates p38 MAPK in animal models,15 16 whether or not p38 MAPK activation in ischemic myocardial tissue is involved in postischemic myocardial apoptosis has not been directly determined. To our knowledge, our results provide the first direct evidence that p38 MAPK is a key factor in signal transduction leading to myocardial apoptosis after ischemia and reperfusion. However, it should be noted that although administration of 10 µmol/L SB 203580 completely blocked p38 MAPK activation, this dose failed to result in complete inhibition of apoptosis induced by ischemia and reperfusion. This results suggest that other signal transduction pathways, such as JNK/SAPK, may also contribute to postischemic myocardial apoptosis.
Another important discovery from the present study is that administration of SB 203580 not only significantly reduced myocardial apoptosis but also significantly improved cardiac function recovery after reperfusion. A likely explanation for the protective effects of SB 203580 is that this compound inhibited the activation of p38 MAPK and blocked a critical component in the signal transduction pathway that leads to apoptotic myocyte death, thus attenuating postischemic myocardial injury and improving cardiac functional recovery. This conclusion is supported by our time-dependent study. Our results demonstrated that the improvement in cardiac function was closely correlated with the inhibition of p38 MAPK. Administration of SB 203580 both before ischemia and during reperfusion completely blocked p38 MAPK activation. This treatment also exerted the best cardioprotective effect. In contrast, when SB 203580 was administered 10 minutes after reperfusion, a time point at which maximal p38 MAPK has already been reached, no protective effect against postischemic cardiac dysfunction was observed. Taken together, our results provide the first direct evidence that inhibition of p38 MAPK and reduction of subsequent myocardial apoptosis are capable of improving heart function after myocardial ischemia and reperfusion.
In addition, we have also demonstrated that administration of SB 203580 significantly attenuated postischemic myocardial necrotic injury. We cannot precisely determine the mechanisms by which SB 203580 reduces myocardial necrosis in this severe pathological model. Although we do not have any direct evidence to support a hypothesis that apoptosis may be followed by necrosis in the same population of cells, it cannot be ruled out that the protective effect of SB 203580 against necrotic injury is related to its ability to reduce early apoptosis in ischemic/reperfused hearts.
In summary, we have demonstrated that myocardial ischemia and reperfusion, a real pathological stress to the heart, results in significant activation of p38 MAPK. We have provided the first direct evidence that activation of p38 MAPK plays a key role in the signal transduction pathway mediating myocardial apoptosis after ischemia and reperfusion. Most interestingly, we have found that inhibiting p38 MAPK, which reduces myocardial apoptosis associated with p38 MAPK activation, significantly improves postischemic cardiac functional recovery. These results provide a likely answer to the critical question of whether or not a reduction of apoptosis can translate into meaningful cardiac functional improvement in ischemic/reperfused hearts. Moreover, these results are potentially of great clinical significance because they may suggest a new treatment for ischemic heart disease.
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Acknowledgments |
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We gratefully acknowledge Ya-Ping Guo and Dr Juan L. Gu for their excellent technical assistance in the biochemical analyses reported in this study.
Received July 28, 1998; revision received November 17, 1998; accepted December 29, 1998.
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S. Sanada, M. Kitakaze, P. J. Papst, H. Asanuma, K. Node, S. Takashima, M. Asakura, H. Ogita, Y. Liao, Y. Sakata, et al. Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors: The Role of Protein Kinase A and p38 Mitogen-Activated Protein Kinase Circulation, August 7, 2001; 104(6): 705 - 710. [Abstract] [Full Text] [PDF]
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D. Tekin, L. Xi, T. Zhao, M. I. Tejero-Taldo, S. Atluri, and R. C. Kukreja Mitogen-activated protein kinases mediate heat shock-induced delayed protection in mouse heart Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H523 - H532. [Abstract] [Full Text] [PDF]
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T. A. Fischer, S. Ludwig, E. Flory, S. Gambaryan, K. Singh, P. Finn, M. A. Pfeffer, R. A. Kelly, and J. M. Pfeffer Activation of Cardiac c-Jun NH2-Terminal Kinases and p38-Mitogen-Activated Protein Kinases With Abrupt Changes in Hemodynamic Load Hypertension, May 1, 2001; 37(5): 1222 - 1228. [Abstract] [Full Text] [PDF]
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R. M. Fryer, P. F. Pratt, A. K. Hsu, and G. J. Gross Differential Activation of Extracellular Signal Regulated Kinase Isoforms in Preconditioning and Opioid-Induced Cardioprotection J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 642 - 649. [Abstract] [Full Text]
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K. Yamashita, J. Kajstura, D. J. Discher, B. J. Wasserlauf, N. H. Bishopric, P. Anversa, and K. A. Webster Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1 Circ. Res., March 30, 2001; 88(6): 609 - 614. [Abstract] [Full Text] [PDF]
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T. C. Zhao, D. S. Hines, and R. C. Kukreja Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial KATP channels Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1278 - H1285. [Abstract] [Full Text] [PDF]
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P. Andreka, J. Zang, C. Dougherty, T. I. Slepak, K. A. Webster, and N. H. Bishopric Cytoprotection by Jun Kinase During Nitric Oxide-Induced Cardiac Myocyte Apoptosis Circ. Res., February 16, 2001; 88(3): 305 - 312. [Abstract] [Full Text] [PDF]
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S. Sanada, M. Kitakaze, P. J. Papst, K. Hatanaka, H. Asanuma, T. Aki, Y. Shinozaki, H. Ogita, K. Node, S. Takashima, et al. Role of Phasic Dynamism of p38 Mitogen-Activated Protein Kinase Activation in Ischemic Preconditioning of the Canine Heart Circ. Res., February 2, 2001; 88(2): 175 - 180. [Abstract] [Full Text] [PDF]
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S. Schneider, W. Chen, J. Hou, C. Steenbergen, and E. Murphy Inhibition of p38 MAPK {alpha}/{beta} reduces ischemic injury and does not block protective effects of preconditioning Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H499 - H508. [Abstract] [Full Text] [PDF]
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R. K. Dubey, D. G. Gillespie, L. C. Zacharia, Z. Mi, and E. K. Jackson A2B Receptors Mediate the Antimitogenic Effects of Adenosine in Cardiac Fibroblasts Hypertension, February 1, 2001; 37(2): 716 - 721. [Abstract] [Full Text] [PDF]
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A. T. SAURIN, J. L. MARTIN, R. J. HEADS, C. FOLEY, J. W. MOCKRIDGE, M. J. WRIGHT, Y. WANG, and M. S. MARBER The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes FASEB J, November 1, 2000; 14(14): 2237 - 2246. [Abstract] [Full Text]
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N. Hayashida, S. Chihara, E. Tayama, S. Yokose, K. Akasu, E. Kai, and S. Aoyagi Effects of angiotensin-converting enzyme inhibitor during warm blood cardioplegia Ann. Thorac. Surg., August 1, 2000; 70(2): 627 - 632. [Abstract] [Full Text] [PDF]
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J. W. Mockridge, A. Punn, D. S. Latchman, M. S. Marber, and R. J. Heads PKC-dependent delayed metabolic preconditioning is independent of transient MAPK activation Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H492 - H501. [Abstract] [Full Text] [PDF]
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D. Talmor, A. Applebaum, A. Rudich, Y. Shapira, and A. Tirosh Activation of Mitogen-Activated Protein Kinases in Human Heart During Cardiopulmonary Bypass Circ. Res., May 12, 2000; 86(9): 1004 - 1007. [Abstract] [Full Text] [PDF]
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J.-i. Abe, C. P. Baines, and B. C. Berk Role of Mitogen-Activated Protein Kinases in Ischemia and Reperfusion Injury : The Good and the Bad Circ. Res., March 31, 2000; 86(6): 607 - 609. [Full Text] [PDF]
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T.-L. Yue, C. Wang, J.-L. Gu, X.-L. Ma, S. Kumar, J. C. Lee, G. Z. Feuerstein, H. Thomas, B. Maleeff, and E. H. Ohlstein Inhibition of Extracellular Signal-Regulated Kinase Enhances Ischemia/Reoxygenation-Induced Apoptosis in Cultured Cardiac Myocytes and Exaggerates Reperfusion Injury in Isolated Perfused Heart Circ. Res., March 31, 2000; 86(6): 692 - 699. [Abstract] [Full Text] [PDF]
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M. A. Bogoyevitch Signalling via stress-activated mitogen-activated protein kinases in the cardiovascular system Cardiovasc Res, March 1, 2000; 45(4): 826 - 842. [Abstract] [Full Text] [PDF]
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C. Depre and H. Taegtmeyer Metabolic aspects of programmed cell survival and cell death in the heart Cardiovasc Res, February 1, 2000; 45(3): 538 - 548. [Abstract] [Full Text] [PDF]
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G. Z. Feuerstein and P. R. Young Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways Cardiovasc Res, February 1, 2000; 45(3): 560 - 569. [Abstract] [Full Text] [PDF]
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M. Rezvani, J.D. Barrans, K.-S. Dai, and C.-C. Liew Apoptosis-related genes expressed in cardiovascular development and disease: an EST approach Cardiovasc Res, February 1, 2000; 45(3): 621 - 629. [Abstract] [Full Text] [PDF]
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H. Yaoita, K. Ogawa, K. Maehara, and Y. Maruyama Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction Cardiovasc Res, February 1, 2000; 45(3): 630 - 641. [Abstract] [Full Text] [PDF]
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S. A. Wadsworth, D. E. Cavender, S. A. Beers, P. Lalan, P. H. Schafer, E. A. Malloy, W. Wu, B. Fahmy, G. C. Olini, J. E. Davis, et al. RWJ 67657, a Potent, Orally Active Inhibitor of p38 Mitogen-Activated Protein Kinase J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 680 - 687. [Abstract] [Full Text]
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V. L. Gabai, A. B. Meriin, J. A. Yaglom, J. Y. Wei, D. D. Mosser, and M. Y. Sherman Suppression of Stress Kinase JNK Is Involved in HSP72-mediated Protection of Myogenic Cells from Transient Energy Deprivation. HSP72 ALLEVIATES THE STRESS-INDUCED INHIBITION OF JNK DEPHOSPHORYLATION J. Biol. Chem., November 22, 2000; 275(48): 38088 - 38094. [Abstract] [Full Text] [PDF]
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H. Han, H. Wang, H. Long, S. Nattel, and Z. Wang Oxidative Preconditioning and Apoptosis in L-cells. ROLES OF PROTEIN KINASE B AND MITOGEN-ACTIVATED PROTEIN KINASES J. Biol. Chem., July 6, 2001; 276(28): 26357 - 26364. [Abstract] [Full Text] [PDF]
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Y. Shizukuda, M. E. Reyland, and P. M. Buttrick Protein kinase C-delta modulates apoptosis induced by hyperglycemia in adult ventricular myocytes Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1625 - H1634. [Abstract] [Full Text] [PDF]
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P. Liao, S.-Q. Wang, S. Wang, M. Zheng, M. Zheng, S.-J. Zhang, H. Cheng, Y. Wang, and R.-P. Xiao p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes Circ. Res., February 8, 2002; 90(2): 190 - 196. [Abstract] [Full Text] [PDF]
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T. C. Zhao, M. M. Taher, K. C. Valerie, and R. C. Kukreja p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart: Involvement of NF-{kappa}B and iNOS Circ. Res., November 9, 2001; 89(10): 915 - 922. [Abstract] [Full Text] [PDF]
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