© 2001 American Heart Association, Inc.
Integrative Physiology |
Role of Phasic Dynamism of p38 Mitogen-Activated Protein Kinase Activation in Ischemic Preconditioning of the Canine Heart
Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published as an abstract (Circulation. 1999;100[suppl I]:I-492) and the 73rd Scientific Sessions of the American Heart Association, New Orleans, La, November 12–15, 2000, and published as an abstract (Circulation. 2000;102[suppl II]:II-212).
From the Department of Internal Medicine and Therapeutics (S.S., M.K., H.A., H.O., K.N., S.T., M.A., J.Y., T.F., A.O., T.K., M.H.), Osaka University Graduate School of Medicine, Suita; Department of Legal Medicine (K.H., K.Y.), Graduate School of Medicine, University of Tokyo, Tokyo; Department of Legal Medicine (T.A., K.Y.), Yamaguchi University School of Medicine, Ube; and Department of Physiological Science (Y.S., H.M.), Tokai University School of Medicine, Isehara, Japan, and Department of Pediatrics (P.J.P., N.T.), National Jewish Medical Research Center, Denver, Colo.
Correspondence to Masafumi Kitakaze, MD, PhD, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan. E-mail kitakaze{at}medone.med.osaka-u.ac.jp
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Abstract |
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Abstract—Although ischemic stress, including ischemic preconditioning (IP), activates p38 mitogen-activated protein kinase (MAPK), the relationship between p38 MAPK activation and the underlying cellular mechanisms of cardioprotection by IP is not verified in vivo. We examined the effects of the selective p38 MAPK inhibition on the cardioprotective effect of IP in the open-chest dogs. The coronary artery was occluded 4 times for 5 minutes, separated by 5 minutes of reperfusion (IP) followed by 90 minutes of occlusion and 6 hours of reperfusion. We infused SB203580 into the coronary artery during IP and 1 hour of reperfusion, during IP alone, and during sustained ischemia in the IP group. p38 MAPK activity markedly increased during IP but did not additionally increase at the onset of ischemia and was even attenuated at 15 minutes of sustained ischemia, and heat-shock protein (HSP) 27 was phosphorylated and translocated from cytosol to myofibril or nucleus without affecting total protein level at the onset of ischemia compared with the control group. SB203580 treatment (1 µmol/L) only during IP blunted the infarct size limitation by IP (37.3±6.3% versus 7.4±2.1% in the IP group, P<0.01) and attenuated either phosphorylation or translocation of HSP27 during IP. Although the SB203580 treatment throughout the preischemic and postischemic periods had no significant effect on infarct size (33.3±9.4%) in this model, treatment with SB203580 only during ischemia partially mimicked the infarct size limitation by IP (26.8±3.5%). Thus, transient p38 MAPK activation during ischemic preconditioning mainly mediates the cardioprotection followed by HSP27 phosphorylation and translocation in vivo in the canine heart.
Key Words: p38 mitogen-activated protein kinase • heat-shock protein 27 • ischemic preconditioning • infarct size • canine heart
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Introduction |
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Brief periods of ischemia, which precede sustained ischemia, limit infarct size markedly, a phenomenon known as ischemic preconditioning (IP).1 2 The underlying mechanisms have been studied extensively.3 4 5 Recent studies on the subcellular mechanisms of ischemia/reperfusion injury revealed that p38 mitogen-activated protein kinases (MAPKs) are phosphorylated and activated by ischemic stress6 7 8 9 10 11 or other stresses.12 13 Importantly, p38 MAPKs transduce the extracellular stimuli to the nuclei or other compartments as well as extracellular signal–regulated kinases (ERKs) or c-Jun N-terminal kinases (JNKs). Furthermore, MAPK-activated protein kinase-2 (MAPKAPK-2), located downstream of p38 MAPK,7 14 is known to phosphorylate 27-kDa small heat-shock protein (HSP27),15 16 17 which plays a protective role18 against ischemic19 or oxidative20 stress. The translocation of HSP27 from cytosol to myofibril or nucleus21 22 may prevent actin fragmentation23 or microtubule degradation.24 Thus, both p38 MAPK and HSP27 might be involved in the pathophysiology in the protection against myocardial ischemia/reperfusion injury. Recently, some studies showed that p38 MAPK activation during IP mediates its beneficial effect,6 7 8 whereas other studies report that the p38 MAPK inhibition during ischemia and reperfusion protects myocardium.9 10 11 However, the cause-and-effect relationship between p38 MAPK activation and the infarct size–limiting effect is not verified in vivo. Therefore, we examined the effect of the selective inhibitor of p38 MAPK, SB203580 (SB), on infarct size, p38 MAPK activity, and HSP27 activation during or after IP using an in vivo infarction model of the canine heart.
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Materials and Methods |
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All procedures were performed in careful conformance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (publication No 85-23, revised 1985).
Instrumentation
Beagle dogs (Oriental Yeast, Tokyo, Japan) weighing 9
to 14 kg were prepared as described
previously.25 In all
experiments, mean arterial blood pressure (ABP), heart rate (HR), and
PO2
in the systemic arterial blood in control conditions averaged 105±2.3
mm Hg, 132±2.4 beats per minute, and 106±2.6 mm Hg, respectively.
Both ABP and HR were measured continuously during the
experiment.
Protocol 1: Effect of p38 MAPK Inhibition on
IP
We used 69 dogs in this protocol.
Figure 1A
indicates all details of the schedules of this
protocol. IP procedure was performed by 4 cycles of 5 minutes of
coronary occlusion and a subsequent 5 minutes of reperfusion by
occluding the bypass tube. Then the coronary artery was occluded for 90
minutes (sustained ischemia) followed by 6 hours of
reperfusion.
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The dose of SB for an intracoronary infusion was 1.18 µg · kg-1 · min-1, theoretically corresponding to 1 µmol/L at the coronary arterial blood. This concentration has been shown in previous studies to specifically inhibit p38 MAPK.9 10 18 20 We used the vehicle dimethyl sulfoxide at a final concentration of <0.15%, which does not influence infarct size.26
Protocol 2: Effect of IP on p38 MAPK
Activity
We used 28 dogs in this protocol.
Figures 1B
and 1C indicate all details of the schedules of
this protocol. We quickly sampled myocardial tissue supplied by the
left anterior descending coronary artery (LAD) into liquid
nitrogen and stored it at -80°C.
To immunoprecipitate p38 MAPK, 1 gram of myocardial tissue was homogenized, and in vitro kinase assay was carried out as described previously.27 A part of the samples were used for the measurement of MAPKAPK-2 using a commercially available immunoprecipitation-kinase assay kit (Upstate Biotechnology).
Protocol 3: Effect of IP on the Phosphorylation
and Translocation of HSP27
We used 19 dogs in this protocol. With or without the
IP procedure, we infused SB (1.18
µg · kg-1 · min-1
intracoronary infusion) or saline into the LAD in the identical manner
with protocol 2 (IP+SB group, n=5; IP group, n=4; SB group, n=5; and
control group, n=5). We quickly sampled myocardial tissue supplied by
the LAD just before the sustained ischemia and stored it at
-80°C.
To evaluate the phosphorylation of HSP27, each specimen was subjected, immunoblotted, and measured as described previously,8 21 with modification, using the antibodies to either HSP27 or phosphospecific HSP27 at Ser 78 (Upstate Biotechnology).
To evaluate the intracellular translocation of HSP27, each specimen in protocol 3 was homogenized, separated into P1 (nuclear and myofibrillar), P2 (membranous), and S (cytosolic) fractions, immunoblotted, and measured as described previously.21 28
Criteria for Exclusion
To ensure that all animals included in the data
analysis of infarct size were healthy and exposed to similar extents of
ischemia, exclusion criteria described
previously25 were
used.
Measurement of Infarct Size and Myocardial
Collateral Blood Flow
We measured infarct size and regional myocardial
blood flow as described
previously,25 with
modification. For randomization of the study, all measurements were
done at the completion of protocol without knowledge of the treatment
in each heart.
Statistical Analysis
Each value was expressed as mean±SEM. Statistical
analysis was performed using ANOVA with Fisher’s post hoc test or
ANCOVA between regional collateral blood flow and infarct size, as
described previously,25 with
P<0.05 indicating a
significant difference.
An expanded Materials and Methods section can be found in an online data supplement available at http://www.circresaha.org.
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Results |
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Mortality and Exclusions
Of 69 dogs that were randomly devoted to 10 groups for assessment of infarct size in protocol 1, 16 dogs developed lethal arrhythmia (ventricular tachycardia or fibrillation) at least once. Among these 16 dogs, lethal arrhythmia to match the exclusion criteria occurred in 4 dogs during 90 minutes of ischemia and 5 dogs during reperfusion after 90 minutes of ischemia. These 9 animals were excluded from assessment of infarct size. In the remaining 60 dogs, 5 were excluded from the data analysis because myocardial collateral blood flow was >15 mL/100 g per min. Therefore, 55 dogs completed the protocols satisfactorily and were used for data analysis.
Changes in Hemodynamic Parameters, Risk Area,
and Collateral Blood Flow
There were no significant differences in mean ABP and
HR among all groups in each experiment. The risk area and collateral
flow at 80 minutes of sustained ischemia were comparable in all groups
in each experiment.
Infarct Size
Figure 2 shows infarct size in the 8 groups in protocol 1
(Figure 2A) and the regression plots of infarct size in
protocol 1 as a percentage of the area at risk against collateral flow
in all groups
(Figure 2B). IP (group 6) markedly attenuated infarct size
compared with the control group (group 1) (7.4±2.1% versus
38.9±4.7%, respectively,
P<0.01). The treatment with
SB, the potent inhibitor of p38 MAPK, only in preischemic phase blunted
the infarct size–limiting effect of IP (37.3±6.3% in the IP+preSB
group [group 8], P<0.01
versus IP), although SB (1.18
µg · kg-1 · min-1)
during ischemia failed to affect the infarct size limitation afforded
by IP (7.9±1.2% in the IP+ischemia SB [IscSB] group [group 7]).
In our preliminary experiments, we observed that the intracoronary
administration of SB (11.8
µg · kg-1 · min-1)
for only 5 minutes before the sustained ischemia did not change the
infarct size in any of the control or IP groups (n=4 each, data not
shown). Furthermore, SB during the preischemic and postischemic periods
failed to protect the myocardium (33.3±9.4% in the SB group [group
4] versus 37.4±4.8% in the vehicle group [group 2]). However, the
treatment with SB (1.18
µg · kg-1 · min-1)
during the sustained ischemia showed the partial but significant
infarct size limitation (26.8±3.5% in the IscSB group [group 5]
versus 41.6±5.8% in the ischemia vehicle [IscVehicle] group [group
3], P<0.05). On the other
hand, treatment with the vehicle did not affect infarct size
attributable to 90 minutes of ischemia followed by 6 hours of
reperfusion during the sustained ischemia (IscVehicle group [group
3]) or during the preischemic or postischemic period (vehicle group
[group 2]) (41.6±5.8% and 37.4±4.8%,
respectively).
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P<0.05 vs IscVehicle group.
p38 MAPK Activity During IP and After Sustained
Ischemia
Figure 3 shows representative cases in p38 MAPK activity
(top left) and MAPKAPK-2 activity (top right) and the mean value for
each group in protocol 2 (bottom). There was a marked increase in p38
MAPK activity during IP. Interestingly, p38 MAPK was no longer
activated at the end of IP procedure and returned to the control
levels. Fifteen minutes after the onset of sustained ischemia, p38 MAPK
activity increased only in the control group, which was attenuated in
the IP group. Furthermore, 20 minutes after the onset of sustained
ischemia, MAPKAPK-2 activation increased when SB compound was
pretreated in the SB group (group 4 in
Figure 1C), whereas it was attenuated when SB compound was
continuously treated during sustained ischemia in the IscSB group
(group 5 in
Figure 1C).
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Phosphorylation and Translocation of HSP27
During IP
Figure 4A shows the representative cases in Western blotting
of total HSP27 in each fraction and of total or phosphorylated HSP27
for 4 groups in protocol 3. In
Figure 4B, the mean values for the amount of HSP27 in each
fraction and the amount of total or phosphorylated HSP27 are indicated
as the relative ratio, compared with the total amount of HSP27 in the
control group. A large portion of HSP27 was distributed to S (cytosol)
fractions but much less to P1 (myofibril or nucleus) and P2 (membrane)
fractions. IP caused the translocation of HSP27 from S to P1 fraction
before sustained ischemia, associated with the increase in the ratio of
phosphorylated HSP27, without any significant increase in the total
amount. This was blocked by SB, which itself did not influence the
HSP27 phosphorylation or translocation.
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Discussion |
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The cardioprotection caused by IP has been intensively investigated basically and clinically, because it has been confirmed that IP limits infarct size.1 2 3 5 7 25 26 Nevertheless, subcellular mechanisms remain unclear despite a great deal of effort by many research groups. In the present study, we clarified that IP causes the phasic increase in P38 MAPK, transient strong activation during IP, and the inhibition after sustained ischemia. Furthermore, transient activation of p38 MAPK during IP, much more than during sustained ischemia or during reperfusion, mediates the infarct size-limiting effect of IP as a trigger through the phosphorylation and translocation of HSP27 to myofibril in in vivo canine heart.
Activation of p38 MAPK During IP
Because p38 MAPK activity shows the phasic pattern
during and after IP and the inhibition of p38 MAPK during sustained
ischemia10 11 or
in early phase of reperfusion after lethal
ischemia9 mediates
cardioprotection, it is likely that the transient activation of p38
MAPK triggers the cardioprotection of IP or that the deactivation of
p38 MAPK after the onset of lethal ischemia mediates cardioprotection.
The present study revealed that the inhibition of p38 MAPK during the
IP procedure using SB completely reverses the infarct size–limiting
effect and that although the intracoronary pretreatment with SB
influences neither infarct size nor the infarct size limitation by IP,
continuous existence of SB during sustained ischemia protects the
myocardium. This observation strongly suggests the important role of
the transient activation of p38 MAPK in the attenuation of
ischemia/reperfusion injury after the IP procedure, as supported by
previous
studies.7 8 10
However, we cannot deny the possibility that the deactivation of p38
MAPK during sustained ischemia may also mediate the cardioprotection of
IP in the present study, which is also supported by several
investigations.9 10 11
In the present study, SB administration before and after 90 minutes of
ischemia did not reduce infarct size as was seen in IP, but the
continuous treatment with SB during sustained ischemia partially
mimicked the infarct size–limiting effect of IP. This observation may
clarify the disparity between the effects of preischemic treatment with
SB and the continuous treatment with SB during sustained ischemia in
the present study. In dogs, there is substantial collateral blood flow;
therefore, the pretreated drug in the ischemic region may be washed
out, thereby showing no significant effect. On the other hand, the
continuous infusion of SB into the ischemic region can avoid the
washout even in the canine hearts, which assures the effect of SB
during sustained ischemia. Therefore, the washout of the drug
attributable to collateral blood flow may account for the disparity in
this model, and SB during ischemia in the present model may also have
the infarct size–limiting effect, as strongly suggested by the
difference in the present study comparing the MAPKAPK-2 activity
between the SB and the IscSB groups during sustained ischemia. This may
also account for the difference between our present observation and a
previous study using the in vivo swine
model,11 because the swine
model has no collateral flow. The evidence of the activation of p38
MAPK during sustained ischemia and the limited effects of SB
administered during sustained ischemia on infarct size in the present
study suggests that there may be additional inhibition of p38 MAPK for
the infarct size-limiting effect of IP in canine hearts during
sustained ischemia. On the other hand, previous
studies7 8 show
that IP increases p38 MAPK activity during sustained ischemia, although
Mackay et al10 and the
present study showed that IP prevents prolonged activation of p38 MAPK
during sustained ischemia. The differences in the activity of p38 MAPK
during sustained
ischemia7 8 9 10 11
may be attributable to the experimental models, protocols for the IP
procedure, species differences, or time of myocardial
ischemia.
The scenario that transient activation of p38 MAPK triggers the infarct size–limiting effect of IP may be quite similar to protein kinase C (PKC) activation, which has been largely accepted to mediate the cardioprotection of IP.25 29 30 31 PKC activation after the onset of reperfusion is no longer cardioprotective, and after this period, PKC inhibition does protect the myocardium.14 Other studies show that p38 MAPK is downstream of PKC,32 which has also yet to be clarified in our model. On the other hand, one recent study33 mentions that SB can also inhibit JNKs in a higher dose, whereas 1 µmol/L of SB is specific for the inhibition of p38 MAPK, suggesting that the modulation of cardioprotection in this study may be independent of JNKs. This is additionally supported in other studies.7 10
Involvement of the Phosphorylation and
Translocation of HSP27 in IP
We also observed that IP increased the translocation of
HSP27 associated with the increase in phosphorylation of HSP27, both of
which were blunted by SB in this model. The observations that HSP27 is
translocated by p38 MAPK
activation21 22 34
or is linked with
cardioprotection18 19 20
are described in some recent studies, although there are other
candidates for pathways that can activate HSP27. Furthermore, the
positive role of HSP27 phosphorylation is also stated in other
systems,15 16 17 18 19 20
and the synchronicity of the phosphorylation and translocation of HSP27
is established in other types of
cells.35 Taking these
findings together, the phosphorylation and translocation of HSP27 may
also occur sequentially in this model. In addition, the overexpression
of HSP27 itself is reported to exert
cardioprotection.36 37
The recent studies investigating the molecular mechanisms of
HSP27-induced cell protection show that HSP27 binds to Z-bands of
myofibrils21 22
or carboxyl-terminal region of the
protein38 and protects
against conformation changes or fragmentation in myofibril and
cytoskelton.24 37
Furthermore, a recent study shows that HSP27 negatively regulates cell
death by preventing the interaction of Apaf-1 with procaspase-9 through
binding with cytochrome-c, which is released from mitochondria and
enhances this
interaction.39
Time Point for the Activation of p38 MAPK Among
Repeated Cycles of a Brief Period of Ischemia
It is important to consider how many cycles of a brief
period of myocardial ischemia are necessary to activate p38 MAPK. To
answer this issue, we should investigate the exact time course of p38
MAPK/HSP27 activation during 4 cycles of ischemia and reperfusion of
the IP procedure in this model. The heart can be sufficiently
preconditioned after first occlusion, and p38 MAPK is fully activated
at the end of the first transient ischemia in IP in the
rabbit.40 Although this may
also be the case in the present model, this has yet to be
clarified.
These findings may indicate that ischemic damages accumulate after the second occlusion of the IP procedure, although the repetition of 5 minutes of ischemia does not cause myocardial injury or impair the IP-induced cardioprotection. Sampling at more frequent time points might clarify this issue.
Clinical Implication
Because the present results suggest that the
phosphorylation and translocation of HSP27 after the transient
activation of p38 MAPK is beneficial, the way to translocate HSP27 may
be essential for the mediation of IP. HSP27 may protect the myofibril
and cytoskeleton, whereas KATP channel opening,
another possible mediator of IP, inhibits calcium overload or improves
energy condition at mitochondria. Therefore, we need to identify the
pharmacological or molecular biological methods, including the gene
transfer to activate HSP27, and we need to use this method in
combination with others to open KATP channels
(eg, nicorandil) in patients with ischemic heart
disease.
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Acknowledgments |
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This study was supported by grants-in-aid for Scientific Research (10557068 and 10670649) from the Ministry of Education, Science, Sports and Culture of Japan and by grants from the Smoking Research Foundation of Japan. We thank H. Koyama, Y. Liao, and J. Fujiki for technical assistance and advice.
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Footnotes |
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Original received July 25, 2000; revision received November 28, 2000; accepted November 29, 2000.
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