© 2000 American Heart Association, Inc.
Clinical Research |
Activation of Mitogen-Activated Protein Kinases in Human Heart During Cardiopulmonary Bypass
From the Division of Anesthesiology (D.T., Y.S.), Department of Cardiothoracic Surgery (A.A.), The S. Daniel Abraham Center for Health and Nutrition (A.R.), and the Department of Clinical Biochemistry (A.T.), Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Correspondence to Amir Tirosh, MD, Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel, IL-84105. E-mail amirt{at}bgumail.bgu.ac.il
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Abstract |
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Abstract—Mitogen-activated protein kinases (MAPKs) have been shown to be activated in both in vitro and in vivo models of cardiac tissue in response to ischemia/reperfusion injury. We investigated whether MAPKs are activated in human heart during coronary artery bypass grafting (CABG) surgery. During elective CABG surgery of 8 patients, 3 right atrial appendage biopsies were obtained at baseline, at the end of cross-clamping, and after coronary reperfusion. The expression of the p38-MAPK, c-Jun N-terminal kinase (JNK), and extracellular signal–regulated kinases (ERK1/2) MAPKs was not altered during CABG. The phosphorylation and activation of both ERK1/2 and p38-MAPK were increased
2-fold by ischemia and
even more (8- and 4-fold, respectively) by reperfusion. Although the
ischemic period did not result in a significant activation of
JNK, an 6-fold increase in JNK activity could be observed after
reperfusion. In conclusion, distinct activation patterns of ERK1/2,
p38, and JNK MAPKs can be observed in human heart during CABG.
Key Words: myocardium • ischemia/reperfusion • stress-activated protein kinases
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mitogen-activated protein kinases (MAPKs) are activated by diverse stimuli and appear to mediate cellular responses including proliferation, differentiation, and adaptation to stress.1 2 Three major subfamilies have been characterized, including the extracellular signal–regulated kinases (ERK1/2), the c-Jun N-terminal kinases (JNK1/2), and the p38-MAPKs.2 It has been previously reported that although the ERKs are mainly involved in mediating anabolic processes such as cell division, growth, and differentiation, the JNKs and the p38-MAPKs are generally associated with cellular response to diverse stresses (reviewed in References 3 and 4 ).
In recent years, the possible importance of MAPK activation in the heart during ischemia/anoxia and reoxygenation has been raised.2 4 The JNKs and the p38-MAPKs have been consistently shown to be activated by myocardial ischemia/reperfusion in both animal models4 5 and in cardiomyocyte cell lines.6 7 The ERKs, however, have been shown to be activated in isolated animal hearts by ischemia/reperfusion by some,5 8 although not all investigators,4 9 possibly in response to oxidative stress.9 10 The exact role of the MAPKs in cardiac pathophysiology in humans has not been fully elucidated, partly because of limited information regarding the activation pattern of the MAPKs in the human heart. A recent study demonstrated the expression of JNK, p38-MAPK, and ERK1/2 in the human heart. A potential clinical relevance for their action was demonstrated by an increased activity of JNK and p38-MAPK in heart failure secondary to ischemic heart disease.11
In the present study, we aimed at evaluating both the expression and activation of the different MAPKs in nonfailing human hearts by cardiopulmonary bypass during the course of coronary artery bypass grafting (CABG) surgery.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study was performed on right atrial appendage samples obtained from patients during elective CABG surgery who were admitted to the Department of Cardiothoracic Surgery at Soroka Medical Center. Biopsies from 5 men and 3 women (mean age 68±12 years) were obtained. The protocol for the study was approved by the institutional ethics committee, and informed consent was obtained from all patients. Patients excluded from the study were those with left ventricular ejection fraction of <0.4, those requiring preoperative inotropic or intra-aortic balloon pump support, and those with uncontrolled systemic diseases (diabetes, hypertension, or renal failure). All patients received antianginotic and antihypertensive medications up until the day of surgery. Routine anesthetic and surgical protocols were used in all patients enrolled, and the same two surgeons used a similar technique to perform all operations. Briefly, blood cardioplegia was administered to all patients after cross-clamping of the aorta. Cardioplegia was given first antegrade, through the aortic root, and then retrograde through the coronary sinus with boluses of cold cardioplegia every 20 minutes. Patients were maintained at mild hypothermia (32°C rectal temperature), and pump flows were adjusted to a nonpulsatile perfusion pressure of 70 to 90 mm Hg. Before removal of the cross-clamp, an additional warm cardioplegia was given, followed by warm blood.
Heart Biopsies and Preparation
Biopsies (40 to 60 mg) were taken into liquid nitrogen at 3 time
points during the operation: (1) during cannulation of the right atrium
(control); (2) at the end of the cross-clamping period
(ischemia); and (3) after reconstitution of coronary
blood flow (reperfusion). The duration of the ischemia and
reperfusion periods for each patient is presented in the Table
.
Samples were powdered under liquid nitrogen and homogenized
in lysis buffer that contained (in mmol/L) Tris-HCl 50 (pH 7.5),
EDTA 1, EGTA 1, NaF 50, sodium ß-glycerophosphate 10, sodium
pyrophosphate 5, activated sodium orthovanadate 1, 0.1% Triton
X-100, and 0.1% 2-mercaptoethanol in the presence of protease
inhibitors. The homogenates were further
processed as previously described.12 Proteins (30 µg)
were separated by SDS–polyacrylamide gel electrophoresis and
subjected to Western blot analysis, using the following
antibodies: anti-JNK1/2, anti–total p38,
anti–dual-phosphorylated p38-MAPK (Sigma, Rehovot,
Israel), anti-ERK2 (Santa Cruz Biotechnology, Inc), and anti–phospho
ERK1/2 (Promega). Quantification was made by video densitometry
analysis, as previously described.12
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Immunoprecipitation and Kinase Assays
ERK was immunoprecipitated using the above-mentioned
antibody, from aliquots of 400-µg protein using standard methods. ERK
activity was assayed using myelin basic protein and
32P
-ATP as substrates. JNK activity was
assayed using the SAP/JNK assay kit (New England Biolabs Inc). Briefly,
JNK was precipitated by c-Jun fusion protein beads, and kinase reaction
was carried out in the presence of nonradiolabeled ATP. In vitro c-Jun
phosphorylation was selectively detected by Western
blot using a phospho-Ser63 c-Jun antibody.
Statistical Analysis
Values are given as mean±SE. The Wilcoxon
nonparametric test for paired values was used for
comparisons between values obtained in control, ischemia, and
reperfusion biopsies.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effect of Myocardial Ischemia and Reperfusion During CABG on Activation of Stress-Responsive (JNK and p38) MAPKs
Although the expression of JNK1/2 was not altered in samples obtained during CABG (data not shown), a significant increase in JNK activity, as measured in an in vitro kinase assay, was observed during reperfusion (5.81±2.74-fold of baseline; P=0.043) (Figure 1
). Regression analysis revealed
a significant inverse correlation (r=-0.69,
P=0.03) of JNK activation compared with basal and the
duration of the reperfusion period. For example, whereas a 5.65-fold
activation over basal was observed after 20 minutes of reperfusion
(patient 2), a 3.96-fold increase could be demonstrated after 79
minutes (patient 3). Consistent with other experimental
models,4–6 only a mild (1.20±0.18-fold), nonsignificant
activation of JNK could be demonstrated in samples obtained during the
ischemia period. Moreover, the length of the ischemic
period (Table
) was not associated with an alteration in the
degree of JNK activation.
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p38-MAPK expression was not altered in human right atrial appendage
samples during CABG (Figure 2A).
Activation of p38-MAPK was evaluated using an antibody directed against
double-phosphorylated p38-MAPK, which was demonstrated
to correlate well with kinase activity13 (and data not
shown). Samples obtained during both ischemia and reperfusion
periods exhibited increased p38-MAPK phosphorylation
compared with baseline samples, revealing 2.19±0.41-fold
(P<0.05) and 4.19±2.11-fold (P<0.05),
respectively (Figure 2B). The difference between the degree of
p38 phosphorylation during ischemia and
reperfusion did not reach statistical significance
(P=0.079). This could be attributed to the high variation
between patients in p38-MAPK phosphorylation state
during reperfusion. Although the highest activation was noted in
samples obtained up to 30 minutes after reperfusion, longer periods
before biopsy collection appeared to result in a lower degree of
phosphorylation, nearly returning to the control level
(patient numbers 3 and 7). Regression analysis revealed a
significant (P<0.01) inverse correlation
(r=-0.94) between the reperfusion period and the degree of
p38-MAPK phosphorylation over basal. These data may
suggest that p38 phosphorylation is transient during
the reperfusion state, reflecting either the transient presence of an
activating factor and/or the existence of an activation-termination
loop. Collectively, these data demonstrate that during the course of
CABG procedure, the stress-responsive MAPKs JNK and p38 are
activated in human heart, displaying a distinct time course of
activation.
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CABG Procedure Results in Activation of ERK1/2 MAPKs
Neither the ischemic period nor reperfusion resulted in
altered ERK1/2 expression (Figure 3A).
The phosphorylation of both ERK1 and ERK2 was increased
in tissue samples obtained during the ischemic period compared
with control (2.07±0.45- and 2.72±0.83-fold, respectively) (Figure 3B). Reperfusion resulted in a further increase in the
phosphorylation of both isoforms, reaching
3.73±0.69-fold for ERK1 and 7.84±1.83-fold for ERK2, compared with
control. Because full activation of ERK1/2 requires dual
phosphorylation of these enzymes, whereas the
phosphospecific antibody is directed only against the first
phosphorylation site (Thr202), ERK1/2 activity was
directly measured using an in vitro kinase assay. As shown in Figure 3C, after ERK1/2 immunoprecipitation, the activity of these
enzymes was highly correlated with the phosphospecific
immunoblot pattern, resulting in 2.33±0.48- and
5.57±2.29-fold over basal, for ischemia and reperfusion,
respectively. As opposed to the inverse correlation between the
duration of the reperfusion period and the degree of JNK and p38-MAPK
activation, no similar correlation could be demonstrated for ERK1/2.
Taken together, these data demonstrate that CABG results in activation
of ERK1/2 in human heart.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we report that during the course of CABG procedure, activation of various members of the MAPK subfamily occurs in human heart. The pattern of activation may differ between the various MAPKs, with JNK being activated primarily by reperfusion (Figure 1
), whereas p38 and ERK1/2 by
ischemia and even more by reperfusion (Figures 2 and 3). The experimental model used in the present study imposes strict intrinsic limitations, including access solely to right atrial appendage tissue and limited sample number and size available. In addition, during the course of the operation, the myocardium is exposed to multiple factors, which include not only ischemia and reperfusion but also alterations in temperature and electrolyte concentrations, as well as various pharmacological agents used during the surgical and anesthetic procedures.
Despite these obvious limitations, the finding of activation of the
stress-responsive MAPKs during CABG is consistent with
observations obtained in various experimental models for
ischemia/reperfusion. In cell culture systems,6 as
well as in ex vivo4 and in vivo5 models, JNK
activation was primarily observed during reperfusion, whereas p38-MAPK
was activated during hypoxia, and this activation was
maintained during the reperfusion period. In the present study, we
demonstrate that both short and prolonged ischemia periods do
not result in significant JNK activation, whereas p38-MAPK is
activated. During reperfusion, both MAPKs are
activated, whereas JNK activation appears to outlive that of
p38-MAPK. Despite the significant inverse correlation between the
duration of the reperfusion period and the degree of JNK or p38-MAPK
activation, a reperfusion period >30 minutes was still associated with
a 4-fold increase in JNK activity compared with control, whereas
p38-MAPK activation decayed to near-control values. Nevertheless, the
possibility that factors other than hypoxia reperfusion
contributed to the activation of JNK and p38-MAPKs during CABG cannot
be ruled out. Specifically, cold exposure,14 alterations
in the intracellular calcium concentration,15 16 and
catecholamines such as
phenylephrine,17 norepinephrine,
and isoproterenol18 have been shown to activate
MAPKs. In particular, these factors may have contributed to the
activation of ERK1/2, which we demonstrate to occur in human heart
during both the ischemia and the reperfusion periods of CABG
(Figure 3). ERK1/2 has been shown to be activated by
reactive oxygen species and ischemia/reperfusion in
noncardiomyocytes,19 as well as in cultured
rat cardiac myocytes,7 H9C2 cardiac muscle
cells,20 rat primary
cardiomyocytes,10 and in vivo animal models of
cardiac ischemia/reperfusion.5 8 However, several
studies indicate that ERK1/2 activation during
ischemia/reperfusion in the heart is limited.4 9
Thus, the specific stimuli involved in ERK1/2 activation during CABG
remain to be elucidated.
Various downstream effectors of the MAPK cascades and their implications to various cellular functions are now being discovered. The possibility that activation of MAPKs during CABG may play a role in clinically relevant outcomes of this common procedure is intriguing. For example, activation of p38-MAPK and heat shock protein 27 by oxidative stress has been demonstrated to result in cytoskeleton disarrangement,21 suggesting a cellular mechanism for reduced cardiac contractility during recovery from CABG. In addition, it has been shown that inhibition of p38-MAPK in perfused rabbit hearts decreases cardiomyocyte apoptosis, resulting in improvement of cardiac function after myocardial ischemia and reperfusion.22 In humans, a recent ex vivo study demonstrated in right atrial appendage biopsies that p38-MAPK is indeed being activated by ischemia/reperfusion.23 More importantly, preincubation of human samples with the p38-MAPK inhibitor SB203580 resulted in improved postischemic force development.23 These data in conjunction with the present study suggest that p38-MAPK activation occurs during CABG and may therefore play a causative role in the impaired contractile function observed after this common procedure. Consistent with this notion are the beneficial effects reported for angiotensin-converting enzyme (ACE) inhibitors administered either before24 or during25 cardiopulmonary bypass on various parameters of myocardial ischemic injury24 25 and on contractile dysfunction and metabolic derangement induced by ischemia and reperfusion.26 These may be mediated by the capacity of ACE inhibitors to prevent MAPK activation.6 Additional larger-scale clinical trials are needed to establish more definitively the role of the MAPKs as potential molecular targets for therapeutic intervention.
In conclusion, the present study demonstrates the activation of MAPKs in human heart during CABG surgery. The availability of right atrial appendage tissue may thus provide an easy and safe method to assess the relevance of MAPK activation to clinically important outcomes of CABG.
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Acknowledgments |
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This study was supported by the Cardiothoracic Surgery Department Research Fund 109292 and by the Dr Heinz-Horst Deichmann Chair in Surgery.
Received February 23, 2000; accepted April 6, 2000.
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References |
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