© 1996 American Heart Association, Inc.
Articles |
Stimulation of the Stress-Activated Mitogen-Activated Protein Kinase Subfamilies in Perfused Heart
p38/RK Mitogen-Activated Protein Kinases and c-Jun N-Terminal Kinases Are Activated by Ischemia/Reperfusion
the National Heart and Lung Institute (Cardiac Medicine), Imperial College of Science, Technology, and Medicine, and the Section of Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, University of London (UK).
Correspondence to Dr Peter H. Sugden, Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.
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Abstract |
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It has recently been recognized that cellular stresses activate certain members of the mitogen-activated protein kinase (MAPK) superfamily. One role of these "stress-activated" MAPKs is to increase the transactivating activity of the transcription factors c-Jun, Elk1, and ATF2. These findings may be particularly relevant to hearts that have been exposed to pathological stresses. Using the isolated perfused rat heart, we show that global ischemia does not activate the 42- and 44-kD extracellular signal–regulated (protein) kinase (ERK) subfamily of MAPKs but rather stimulates a 38-kD activator of MAPK-activated protein kinase-2 (MAPKAPK2). This activation is maintained during reperfusion. The molecular characteristics of this protein kinase suggest that it is a member of the p38/reactivating kinase (RK) group of stress-activated MAPKs. In contrast, stress-activated MAPKs of the c-Jun N-terminal kinase (JNK/SAPKs) subfamily are not activated by ischemia alone but are activated by reperfusion following ischemia. Furthermore, transfection of ventricular myocytes with activated protein kinases (MEKK1 and SEK1) that may be involved in the upstream activation of JNK/SAPKs induces increases in myocyte size and transcriptional changes typical of the hypertrophic response. We speculate that activation of multiple parallel MAPK pathways may be important in the responses of hearts to cellular stresses.
Key Words: mitogen-activated protein kinase • stress-activated mitogen-activated protein kinase • c-Jun N-terminal kinase • p38/reactivating kinase • ischemia/reperfusion
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Introduction |
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The ventricular myocyte is a terminally differentiated cell that responds to appropriate external stimuli by adaptive growth in the absence of cell division (hypertrophy).1 In vivo, the myocyte may be exposed to a variety of cellular stresses, such as hypoxia, ischemia, and ischemia/reperfusion.2 3 Although myocytes in the ischemic region may die, the surviving myocytes may hypertrophy to compensate for lost contractile capacity.4 5 Some cellular stresses, such as hypoxia and ischemia/reperfusion, induce transcriptional changes in the heart (eg, increased c-fos and c-jun expression).6 7 Increased expression of these proto-oncogenes is one of the characteristics of the hypertrophic response,1 and noncytotoxic levels of stress could possibly initiate this adaptation. Equally, short periods of ischemia protect the heart against subsequent ischemic episodes ("ischemic preconditioning").8 9 It is thus clear that pathological stresses encountered in vivo have profound effects on the heart.
In a variety of noncardiac cells, it has recently been recognized that cellular stresses activate two separate MAPK cascades, the JNK/SAPK and the p38/RK cascades (see References 10 and 11 and the Table
). These act in parallel to the ERK MAPK cascade12 13 14 15 that is involved in intracellular signaling from receptor protein tyrosine kinases or certain G protein–coupled receptors in the heart.16 17 JNK/SAPK was first identified as a 54-kD protein Ser/Thr kinase activated in necrotic livers of cycloheximide-treated rats,18 and a family of these protein kinases has been subsequently cloned.19 20 21 22 Unlike the ERKs, the JNK/SAPKs are weakly activated by growth factors, phorbol esters, or activated Ras but are strongly activated by inflammatory cytokines and cellular stresses such as UV radiation, heat shock, or low concentrations of protein synthesis inhibitors.20 21 23 24 25 26 27 We have recently shown that JNK/SAPKs are potently activated in neonatal rat ventricular myocytes exposed to osmotic shock or the protein synthesis inhibitor anisomycin.28 Although endothelin-1 activates the JNK/SAPKs, it is much less effective than osmotic shock or anisomycin, and phorbol esters are ineffective.28
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The second group of stress-activated MAPKs recently identified are the mammalian homologues of Xenopus Mpk2 and the Saccharomyces cerevisiae osmosensing protein kinase HOG1. They have been referred to as p38,29 30 RK,31 32 or cytokine-suppressive anti-inflammatory drug–binding protein.33 These protein kinases are also poorly activated by mitogens but potently activated by endotoxin, osmotic shock, heat shock, or metabolic inhibitors such as sodium arsenite.29 31 34
There is a considerable body of evidence that the activation of the ERK cascade is involved in the hypertrophy of the ventricular myocyte.17 The hypertrophic phenotype is characterized by increased cell size and myofibrillar complement and is accompanied by expression of immediate-early genes (c-fos, c-jun, and Egr-1), upregulation of constitutively expressed myofibrillar protein genes (
-MHC, cardiac -actin, and vMLC-2), and reexpression of fetal genes (ANF, ß-MHC, and SkM -actin).1 Endothelin-1, 1-adrenergic agonists, and phorbol esters are powerfully hypertrophic1 and potently activate the ERK cascade in ventricular myocytes.35 36 On the basis of this correlation, we proposed a role for ERK in the hypertrophic response induced by these stimuli.35 36 Transient transfection experiments have supported this hypothesis.37 38
The activation of parallel MAPK cascades may be particularly pertinent to the transcriptional regulation in the heart because MAPKs phosphorylate and increase the transactivating/DNA-binding activity of several transcription factors. Specifically, ERKs phosphorylate Elk1,39 40 41 whereas JNK/SAPKs phosphorylate the transactivation domains of c-Jun,23 Elk1,42 and ATF2.22 43 44 Thus, JNK/SAPKs may modulate transcriptional changes at a variety of promoters. p38/RK phosphorylates and regulates ATF2.45 In addition, p38/RK acts in a kinase cascade in which it phosphorylates and activates MAPKAPK2 (originally identified as an ERK substrate46 ), which then phosphorylates the small HSPs, Hsp25/HSP27.47 These HSPs have chaperone-like properties,48 and their expression is increased after brief ischemia.49
We have examined the activation of ERKs, JNK/SAPKs, and p38/RK in hearts exposed to ischemia and to ischemia/reperfusion. We have also studied whether transient transfection of neonatal ventricular myocytes with a constitutively activated MAPK kinase kinase, MEKK1, induces transcriptional and morphological changes. Although MEKK1 was initially thought to be a MAPK kinase kinase for the ERK cascade,50 it is now thought to be involved principally in the activation of the JNK/SAPK cascade.51 52 The results suggest that the activation of stress-activated MAPK cascades may be important in hypertrophy of the ventricular myocyte and/or in other processes (ischemic preconditioning, cell death) in the heart.
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Materials and Methods |
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Heart Perfusions
Adult male (250- to 300-g) Sprague-Dawley rat hearts were perfused retrogradely at a pressure of 10 kPa (70 mm Hg) with Krebs-Henseleit bicarbonate-buffered saline containing (mmol/L) NaHCO3 25, NaCl 119, KCl 4.7, CaCl2 2.5, MgSO4 1.2, and KH2PO4 1.2 (pH 7.6 at 37°C) supplemented with 10 mmol/L glucose and equilibrated with 95% O2/5% CO2. The temperature of the perfusates and hearts was maintained at 37°C by the use of a water-jacketed apparatus. After equilibration (15 minutes), the perfusion was interrupted for 1 to 30 minutes by clamping the aortic perfusion line, and the hearts were thus rendered globally ischemic. Hearts ceased beating within 1 minute of ischemia. Where indicated, ischemic hearts were reperfused for 1 to 30 minutes by reopening the aortic perfusion line. Hearts resumed beating within 1 minute of reperfusion, and coronary flow returned to within 80% of control values (control, 13 mL/min per heart; reperfused, 11 mL/min per heart). Control hearts were perfused for up to 40 minutes after the preequilibration period without interruption to the perfusate flow.
Tissue Extraction
At the completion of the perfusion protocol, heart ventricles were "freeze-clamped" using aluminum tongs precooled in liquid N2 and pulverized under liquid N2. The powders were resuspended in 4 vol of ice-cold lysis buffer A (20 mmol/L HEPES, 2.5 mmol/L MgCl2, 0.1 mmol/L EDTA, 20 mmol/L ß-glycerophosphate, 0.05% [vol/vol] Triton X-100, 0.5 mmol/L DTT, 0.1 mmol/L Na3VO4, 4 µg/mL leupeptin, and 200 µg/mL PMSF, pH 7.7) containing 75 mmol/L NaCl. Extracts were incubated on ice for 5 minutes and then centrifuged (10 000g, 5 minutes, 4°C). The detergent-soluble supernatant fractions were retained, and protein content was measured.53
Assay of Protein Kinase Activities
For analysis of protein kinase activation using the "in-gel" method, detergent-soluble extracts were boiled in SDS-PAGE sample buffer.54 In-gel MBPK assays used 0.5 mg/mL MBP polymerized in 10% (wt/vol) acrylamide-SDS gels.35 36 Protein loading of the extracts was 100 µg per lane. Protein kinases were not detected in control experiments in which substrate proteins were absent from the gel. To assay other protein kinases by this method, MBP was replaced with 0.5 mg/mL recombinant GST fusion proteins (amino acids 46 to 400 of the catalytic region of MAPKAPK2 [GST-MAPKAPK246-400] or amino acids 1 to 135 of the N-terminal transactivation domain of c-Jun [GST–c-Jun1-135]). For the assay of p38/RK, GST-MAPKAPK246-600 was polymerized in 12% (wt/vol) acrylamide-SDS gels. The GST fusion proteins, GST-MAPKAPK246-400 and GST–c-Jun1-135, were expressed in Escherichia coli and purified by glutathione-Sepharose (Pharmacia) chromatography.
For analysis of protein kinases that bind and phosphorylate MAPKAPK2 or c-Jun ("pull-down" assays), detergent-soluble extracts (100 µL, 0.5 mg protein) were added to 160 µg of GST-MAPKAPK246-400 or GST–c-Jun1-135, respectively. After incubation (4°C, 1 hour), glutathione-Sepharose was added, and the incubation was continued with mixing (4°C, 1 hour). Pellets were washed in lysis buffer A containing 75 mmol/L NaCl, then in buffer A (mmol/L: HEPES 20, MgCl2 2.5, EDTA 0.1, and ß-glycerophosphate 20, pH 7.7) containing 75 mmol/L NaCl and 0.05% (vol/vol) Triton X-100, and finally in buffer A alone. Phosphorylation of GST-MAPKAPK246-400 by p38/RKs or phosphorylation of GST–c-Jun1-135 by JNK/SAPKs was initiated with 30 µL of kinase assay buffer (mmol/L: HEPES 20, MgCl2 20, ß-glycerophosphate 20, DTT 2, and Na3VO4 0.1, pH 7.6) containing 20 µmol/L ATP and 1 to 2 µCi [
-32P]ATP (Amersham International). After 20 minutes at 30°C, the reaction was terminated by centrifugation. The pellet was washed in cold buffer A containing 75 mmol/L NaCl and 0.05% (vol/vol) Triton X-100. Phosphorylated proteins in the pellet were eluted by boiling in SDS-PAGE sample buffer and then separated by SDS-PAGE. Gels were stained with Coomassie blue to identify the 65-kD GST-MAPKAPK246-400 or the 46-kD GST–c-Jun1-135. After autoradiography, 32P incorporation was determined by Cerenkov counting of the excised bands. A unit of either kinase transfers 1 pmol 32P per minute into the substrate. Results are expressed relative to the total extract protein incubated with the recombinant proteins.
To analyze MAPKAPK2 activity by FPLC, detergent-soluble heart extracts (0.2 mL) were applied to a Mono S HR5/5 column equilibrated with 25 mmol/L ß-glycerophosphate, 2 mmol/L EDTA, and 5% (vol/vol) glycerol, pH 7.3, containing 0.1% (vol/vol) Triton X-100, 50 µg/mL PMSF, and 0.5 mmol/L DTT. After the column was washed with 5 mL of equilibration buffer (1 mL/min), proteins were eluted with a linear NaCl gradient. Fractions (1 mL) were assayed by incubating 10 µL with 20 µL of kinase assay buffer containing 20 µmol/L ATP, 1 µCi [-32P]ATP, 1 µmol/L peptide inhibitor of cAMP-dependent protein kinase (TTYADFIASGRTGRRNAIHD, Bachem), and 30 µmol/L KKLNRTLSVA substrate31 for 30 minutes at 30°C. The reactions were terminated by pipetting 20-µL samples onto P81 papers, which were immersed in 75 mmol/L H3PO4. The papers were then washed (three times for 10 minutes each) in 75 mmol/L H3PO4, and incorporation of 32P was estimated by Cerenkov counting.
To analyze JNK activity by FPLC, detergent-soluble heart extracts (0.3 mL) were applied to a Mono Q HR5/5 column equilibrated with 50 mmol/L Tris/HCl, 2 mmol/L EDTA, 5% (vol/vol) glycerol, and 0.3 mmol/L Na3VO4, pH 7.5, containing 0.1% (vol/vol) Triton X-100, 200 µg/mL PMSF, and 0.5 mmol/L DTT. After the column was washed with 5 mL of equilibration buffer (1 mL/min), proteins were eluted with a linear NaCl gradient. Fractions (1 mL) were assayed by incubating 10 µL with 20 µL of kinase assay buffer containing 20 µmol/L ATP, 1 µCi [-32P]ATP, and 30 µg GST–c-Jun1-135 for 30 minutes at 30°C. The reaction terminated with SDS-PAGE sample buffer, and incorporation of 32P into GST–c-Jun1-135 was determined by SDS-PAGE as described above.
To assay JNK1 immunocomplex protein kinase activity, detergent-soluble heart extracts were prepared in lysis buffer B (10 mmol/L Tris-HCl, 5 mmol/L EDTA, 50 mmol/L NaF, and 50 mmol/L NaCl, pH 7.4, containing 1% [vol/vol] Triton X-100, 0.1% [wt/vol] fatty acid–free bovine serum albumin, 20 µg/mL aprotinin, and 2 mmol/L Na3VO4). After incubation on ice for 10 minutes, the lysate was centrifuged (10 000g, 10 minutes, 4°C). Affinity-purified rabbit polyclonal antibodies raised against the 17–amino acid peptide (KNGVIRGQPSPLAQVQQ) derived from the C-terminus of human JNK155 and the immunizing peptide were from Santa Cruz Biotechnology Inc. After the JNK1 antibody (20 µL) was added to an aliquot (200 µL) of the detergent-soluble heart extract, these were incubated with mixing for 1 hour at 4°C. Protein A–Sepharose (Sigma) was added, and the incubation was continued for 1 hour at 4°C. The pellets were then washed three times in the lysis buffer B and then twice in 50 mmol/L Tris-HCl, 0.1 mmol/L EGTA, 0.5 mmol/L Na3VO4, and 0.1% (vol/vol) 2-mercaptoethanol, pH 8.0. The immunoprecipitates of JNK1 were assayed by either the in-gel method using GST–c-Jun1-135 as substrate or by resuspending in 30 µL of kinase assay buffer containing 20 µmol/L ATP, 30 µg GST–c-Jun1-135, and 1 µCi [-32P]ATP. In the latter case, the reaction was incubated for 20 minutes at 30°C with intermittent mixing and then terminated by centrifuging the immunoprecipitated kinases from the reaction mixture. An aliquot of the supernatant was mixed with SDS-PAGE sample buffer. Incorporation of 32P into GST–c-Jun1-135 was determined by SDS-PAGE as described above.
Promoter Activation and Measurement of Cell Size in Transiently Transfected Neonatal Rat Ventricular Myocytes
Myocytes, prepared from the ventricles of neonatal rats,56 were plated at a density of 350 cells/mm2. Transfection, 24 hours after initial plating, used a calcium phosphate precipitation method with 15 µg luciferase reporter, 4 µg ß-galactosidase expression plasmid, and a total of 10 µg test plasmids.38 The luciferase reporters used have been reported in detail previously38 and included the promoters of the rat ANF gene (nucleotides -638 to +62), the rat ß-MHC gene (nucleotides -667 to +38), and the chicken SkM -actin gene (nucleotides -394 to +24). In addition, luciferase expression regulated by a region surrounding the mouse c-fos SRE (nucleotides -318 to -291) placed upstream from the minimal c-fos promoter (nucleotides -56 to +109)38 or by a phorbol ester–sensitive promoter from rat containing two AP-1 sites upstream from the minimal prolactin promoter (nucleotides -36 to +34)38 was studied. The test plasmids were active Ras (V12-HRas, in a pEXV3 vector), constitutively active MEKK1 (
N-MEKK1, amino acids 367 to 672 of MEKK150 preceded by an N-terminal myc tag, in a pMT2 vector), and SEK1 (-SEK1, SEK1 in which there is an N-terminal -helical deletion, in a pEF vector). In MEK1, an analogous -helical deletion increases the activity of the enzyme over the wild type.57 The -SEK1 construct was a gift from J.R. Woodgett (Ontario Cancer Institute, Toronto, Canada).
The transfection efficiency was measured after 48 hours by the proportion of myocytes expressing ß-galactosidase. Briefly, cells were washed twice in cold PBS, fixed in 4% (vol/vol) formaldehyde in PBS for 10 minutes at room temperature, and then stained with 0.2 g/L X-gal in PBS containing 5 mmol/L K4Fe(CN)6, 5 mmol/L K3Fe(CN)6, and 2 mmol/L MgCl2. The cells expressing ß-galactosidase activity (blue-stained cells) were randomly selected from all areas of the dishes. For any given experiment, the proportion of blue cells was constant at 2% of the total number of cells counted in 100 fields. Luciferase activity was measured as described previously.38 To facilitate comparison, the results are presented as the relative increase of luciferase activity above that for the empty vector control. This controls for the effects of the transfection protocol and the empty vector alone. The control raw light units for the reporter constructs in the presence of the appropriate empty vectors are given in the text.
Cell size and organization of vMLC-2 into myofilaments were determined for myocytes cultured at a density of 200 000 cells per well in Permanox two-well chamber slides precoated with 5 µg laminin/cm2. Cell areas were determined by planimetry of individual transfected cells (X-gal–stained as described above) in high-power fields. To analyze the organization of contractile proteins into the myofilaments, cells were fixed as described above but then permeabilized (0.3% [vol/vol] Triton X-100 in PBS, 10 minutes, room temperature). Nonspecific sites were blocked (10% [vol/vol] horse serum in 0.3% [vol/vol] Triton X-100 in PBS, 10 minutes, room temperature). vMLC-2 was identified by immunostaining with a polyclonal rabbit anti–vMLC-2 antibody58 and indirect visualization with a Texas Red–linked anti-rabbit Ig antibody. For these studies, transfected cells were identified by immunostaining with a monoclonal mouse anti–ß-galactosidase antibody visualized with streptavidin-7-amino-4-methyl-coumarin 3-acetate.
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Activation of MBPKs by Ischemia and Ischemia/Reperfusion
We have shown previously that the in-gel MBP phosphorylation assay provides a sensitive method for detection of ERK activation in the perfused adult rat heart.59 Using this assay, we investigated the stimulation of ERKs in the perfused heart by pathologically important forms of cell stress, namely, ischemia and ischemia/reperfusion. We could not detect any activation of the 42- or 44-kD ERKs either by ischemia or by ischemia/reperfusion (Fig 1
). However, these assays indicated that 20 minutes of ischemia activated a 38-kD MBPK (MBPK-38) (Fig 1). Activation of MBPK-38 was maintained during ischemia/reperfusion, and a 55-kD MBPK (MBPK-55) was additionally activated (Fig 1). In control experiments, we showed that the time course of activation of MBPK-38 varied somewhat between hearts and required from 8 to 15 minutes of ischemia to attain maximal activity (results not shown). MBPK-38 was also activated by osmotic stress in hearts perfused with Krebs-Henseleit buffer containing 0.5 mol/L sorbitol and comigrated with MBPK-38 activated by ischemia and ischemia/reperfusion (results not shown). These experiments are difficult to interpret because 0.5 mol/L sorbitol not only osmotically shocks the heart but also reduces coronary flow and renders the heart ischemic.
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Activation of Stress-Activated MAPKs
The electrophoretic mobilities of MBPK-38 and MBPK-55 suggested that they may be members of the p38/RK and the JNK/SAPK subfamilies of the MAPK family,11 respectively. Therefore, we examined the activation of p38/RKs or JNK/SAPKs by ischemia and ischemia/reperfusion. Using the in-gel kinase method with GST-MAPKAPK246-400 as a substrate, we observed that either 10- or 20-minute ischemia activated a 38-kD kinase (Fig 2, top; RK-38). The phosphorylation of GST-MAPKAPK246-400 by the 38-kD kinase was greater than the phosphorylation of MBP (Fig 1
and Fig 2, top), presumably reflecting the substrate preference of this kinase.60 In control experiments, we showed that the activation of this 38-kD MAPKAPK2 kinase occurred in parallel to that of MBPK-38 and similarly required from 8 to 15 minutes of ischemia to attain maximal activity (results not shown). Activity of p38/RK was maintained during reperfusion (Fig 2, top). Weak phosphorylation of GST-MAPKAPK246-400 by protein kinases of 
46 and 55 kD was also observed in the reperfused hearts (Fig 2, top).
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), 20-minute ischemic hearts (
), or hearts made ischemic for 20 minutes followed by 20 minutes of REP (
) were analyzed by FPLC on Mono S. A single major peak of MAPKAPK2 activity in ischemic or reperfused heart extracts was eluted by a linear NaCl gradient (dotted line). Profiles are typical of two sets of perfusions for each treatment.
Protein kinases often interact strongly with their physiological substrates.23 Proteins in the extracts of ischemic or ischemic/reperfused hearts were allowed to associate with GST-MAPKAPK246-400, and the complexes were precipitated with glutathione-Sepharose. After incubation of the precipitates with [-32P]ATP, we demonstrated that both ischemia (20 minutes) and ischemia (20 minutes)/reperfusion (20 minutes) activated a MAPKAPK2 kinase in these pull-down assays (Fig 2, middle). To establish that a downstream target of p38/RK (MAPKAPK2) was activated by ischemia and ischemia/reperfusion, we examined the activities of MAPKAPK2 in heart extracts separated by FPLC on Mono S columns. A single peak of activity eluting at 180 mmol/L NaCl was activated in extracts of ischemic or ischemic/reperfused hearts (Fig 2, bottom). This profile is typical of MAPKAPK2.31 In the absence of ERK activation (Fig 1), the MAPKAPK2 kinase characterized in Fig 2, top and middle, presumably corresponds to the previously characterized 38-kD RK.31 Further molecular characterization of the activator of MAPKAPK2 as the previously characterized RK was hampered by the unsuitability of commercially available antiserum for immunoprecipitation protocols.
To assay JNK/SAPK, we used the in-gel kinase method with GST–c-Jun1-135 as substrate. In contrast to RK (Fig 2, top and middle), ischemia alone for up to 20 minutes did not activate JNK/SAPKs (Fig 3, top left). In control experiments, ischemia alone for up to 40 minutes did not activate JNK/SAPKs (results not shown). However, 46-kD and 55-kD JNKs (JNK-46 and JNK-55) were activated by ischemia/reperfusion (Fig 3, top left), with 10 to 20 minutes of reperfusion being necessary to detect activation after 10 minutes of ischemia (results not shown). Pull-down assays using GST–c-Jun1-135 confirmed that ischemia (20 minutes)/reperfusion (20 minutes), but not 20 minutes of ischemia alone, activated JNK/SAPKs (Fig 3, bottom left).
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Further characterization of JNK/SAPKs by FPLC of heart extracts on Mono Q showed that JNKs eluting at 100 mmol/L and 225 mmol/L NaCl were activated by ischemia (20 minutes)/reperfusion (20 minutes) (Fig 3, top right). As demonstrated by in-gel GST–c-Jun1-135 kinase assays, the activity eluting at 100 mmol/L NaCl corresponded to JNK-46, whereas that eluting at 225 mmol/L NaCl corresponded to JNK-55 (results not shown). Other stresses such as osmotic shock induced by 0.5 mol/L sorbitol or bradycardia/cardiac arrest induced by 50 µmol/L 2-chloroadenosine activated both JNK/SAPK (as shown by in-gel GST–c-Jun1-135 kinase assays) and MBPK-38 (presumably p38/RK, in-gel MBPK assays) in perfused hearts (results not shown). The problems of ischemia induced by perfusion with 0.5 mol/L sorbitol have been mentioned earlier. Thus, ischemia is the only intervention identified in the present study that activates the p38/RK, the MAPKAPK2 kinase, in the absence of JNK/SAPK activation. Furthermore, this occurs in the absence of ERK activation (Fig 1).
We further characterized the JNKs using an antibody directed against the C terminus of human JNK1 (KNGVIRGQPSPLAQVQQ, Santa Cruz Biotechnology Inc). Immunocomplex kinase assays with GST–c-Jun1-135 as substrate showed that ischemia (20 minutes)/reperfusion (20 minutes) stimulated JNK/SAPK activities by sevenfold (results not shown). Furthermore, when the immunoprecipitated kinases were analyzed by the in-gel kinase method with GST–c-Jun1-135 as substrate, both kinases (JNK-46 and JNK-55) were present, although the predominant kinase was JNK-46 (Fig 3, middle right). The specificity of this interaction was demonstrated by the competition of binding by the control immunizing peptide (KNGVIRGQPSPLAQVQQ) (Fig 3, bottom right). Furthermore, no JNK activity was present in reactions performed in the absence of the antibody (Fig 3, bottom right). Thus, JNK-46 may correspond to JNK119 and SAPK.20 The characterization of JNK-55 will require the use of other specific antibodies, but the molecular mass of this kinase determined by in-gel analysis suggests that it may correspond to JNK255 and SAPKII.20
Stimulation of Promoter Activity and Increase in Cell Size by Activated MEKK1 and SEK1
Although originally identified as a MAPK kinase kinase for the ERK cascade,50 MEKK1 is now thought to be the MAPK kinase kinase responsible for the physiological activation of the JNK/SAPK cascade.51 52 The intermediate between MEKK1 and JNK/SAPK is thought to be the MAPK kinase, SEK1.52 Thus, to investigate the potential involvement of the JNK/SAPK cascade in the hypertrophic response, promoter activities of the hypertrophic "marker" genes, ANF, ß-MHC, and SkM -actin, were measured in cultured ventricular myocytes transfected with constitutively active MEKK1 (N-MEKK1). A similar approach has implicated the Ras
c-RafMEKERK cascade in hypertrophy.38 61 62 63 Under control conditions in the presence of the empty backbone vector for N-MEKK1 (ie, pMT2), the luciferase activities of the reporters (in light units emitted in 4 seconds) were as follows: ANF, 12650±1627; ß-MHC, 2030±247; and SkM -actin, 43164±4353. N-MEKK1 stimulated the promoter activity for ANF, ß-MHC, and SkM -actin by 6- to 18-fold (Fig 4, top left), and the extent of activation was not dependent on the luciferase activities of the various reporters measured under control conditions. These results suggest that MEKK1 may regulate signaling cascades controlling changes in expression of these indices of hypertrophy.
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The AP-164 site is a consensus sequence in the promoter regions of many genes, including those whose expression is increased during hypertrophy (eg, ANF and vMLC-265 ). c-Jun participates in transactivation at the AP-1 sites by forming either a homodimer or a heterodimer with c-Fos,66 67 the transactivating activity of the complex being regulated by the phosphorylation of c-Jun66 by the JNK/SAPKs.64 68 69 Expression of the AP-1–regulated reporter was also stimulated by 85-fold by MEKK1 (control AP-1–regulated luciferase activity with backbone vector, 10290±1947 light units emitted per 4 seconds). In contrast, the SRE-regulated c-fos promoter lacking its AP-1 site was upregulated only 6-fold by MEKK1 (control SRE-regulated luciferase activity with backbone vector, 6604±304 light units emitted per 4 seconds). Thus, as predicted, if it participates in the JNK/SAPK cascade, MEKK1 potently stimulates transcription regulated by the AP-1 site.
To investigate the signaling pathway used by MEKK1, we examined the regulation of the ANF promoter in more detail (Fig 4, middle left) by cotransfecting MEKK1 and SEK1 from the MEKK1SEK1JNK/SAPK pathway. As shown in Fig 4, middle left, -SEK1 did not activate ANF promoter activity (control empty vector [pMT2+pEF]–transfected ANF promoter–regulated luciferase activity, 10067±1047 light units emitted per 4 seconds). However, as shown in Fig 4, middle left, the ANF promoter activity was synergistically stimulated by cotransfection of N-MEKK1 with -SEK1.
The small G protein Ras is involved in the activation of the RafMEKERK pathway.70 71 As previously shown by Thorburn et al,61 V12-HRas stimulated ANF promoter activity (control empty vector [pMT2+pEXV3]–transfected basal ANF promoter–regulated luciferase activity, 2703±1357 light units emitted per 4 seconds) (Fig 4, middle left). This was similar to the effect of N-MEKK1+-SEK1 (Fig 4, middle left). The effect of N-MEKK1 was additive with the effect of Ras (Fig 4, middle left). Thus, the Rasc-RafMEKERK and the MEKK1SEK1JNK/SAPK pathways may both contribute to transcriptional changes associated with hypertrophy.
Although the ERK cascade initiates the transcriptional changes typical of the hypertrophic response, activation of the ERK cascade fails to cause myofibrillogenesis37 63 or to increase cell size.38 To examine whether the JNK/SAPK pathway could initiate these morphological changes, myocytes were transfected with N-MEKK1, V12-HRas, or N-MEKK1+V12-HRas, and cell areas were measured. Transfection with N-MEKK1, V12-HRas, or N-MEKK1+V12-HRas doubled the area of the transfected cells (Fig 4, bottom left). This response was similar to that observed after treatment with the hypertrophic agonist phenylephrine for 48 hours (Fig 4, bottom left). The morphology of myocytes was examined by immunostaining with an anti–vMLC-2 antibody, and typical myocytes are shown in Fig 4, right. The myocytes that had been successfully transfected with N-MEKK1 (or empty pMT2 vectors in control and phenylephrine-treated cells) were identified by parallel indirect immunostaining with an anti–ß-galactosidase antibody and are indicated in Fig 4, right, by arrows. Other myocytes in the fields were not transfected. Although the myocytes transfected with N-MEKK1 were larger, no apparent increase in organization of the myofilaments was observed at 48 hours after transfection. This contrasts with the increased organization observed upon treatment of the myocytes with phenylephrine for 48 hours (Fig 4, right). The N-MEKK1–transfected cells were also more irregular in shape than the phenylephrine-treated cells (Fig 4, right). (Note that control and phenylephrine-treated cells were transfected with empty vector to ensure that this did not interfere with the responses.) There is clearly an additional component required before hypertrophy can occur.
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Discussion |
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Ischemic heart disease and acute myocardial infarction are major causes of morbidity and mortality. Reactive hypertrophy of myocytes and ventricular remodeling frequently follow the myocardial damage caused by ischemia and ischemia/reperfusion.72 73 In nonfatal infarctions, the surviving ventricular myocytes adapt hypertrophically to replace the contractile capacity lost through myocyte cell death.74 This reactive hypertrophy assists in maintaining the cardiac output. It is likely that some of the growth effects of cell stress involve modulation of transcription factor activity in which the MAPKs participate. Here, we studied the activation of two subfamilies of stress-activated MAPKs by ischemia and ischemia/reperfusion.
The present study is the first to demonstrate that a protein kinase with characteristics of p38/RK, a recently identified stress-activated MAPK,31 can be chronically activated in the ischemic heart and that activation is maintained during the ensuing reperfusion (Fig 2, top and middle). A second stress-activated MAPK cascade that includes the JNK/SAPKs20 is activated only during reperfusion following ischemia (Fig 3). In contrast, the ERK family of MAPKs is not activated by either ischemia or ischemia/reperfusion (Fig 1). In the heart, activation of ERKs is thus probably coupled preferentially to activation of Gq protein receptors (and additionally, receptor tyrosine protein kinases)17 36 rather than to "stress receptors."
The initiating signals and "stress receptors" in ischemia and in reperfusion following ischemia are likely to be complex and have not yet been identified. Differences in these initiating signals or the initial upstream regulation of the two stress-activated MAPK pathways must exist to account for the differential activation of the JNK/SAPKs and the MAPKAPK2 activator, p38/RK. Possible initiating signals may include the osmotic imbalances caused by ischemia2 or the release of reactive oxygen species during reperfusion.3 We also showed that contractile arrest or hyperosmotic shock activates both the p38/RK and JNK/SAPK pathways. Thus, ischemia is the only intervention that we have so far identified that selectively activates the p38/RK cascade.
Recent studies have demonstrated translocation (hence, presumably, activation) of PKC during ischemia, although this translocation is rapidly reversible upon reperfusion.75 76 The extent of PKC translocation induced by ischemia75 is relatively small compared with that induced by phorbol esters,54 77 which directly activate PKC, or with physiological agonists such as endothelin-1 or phenylephrine.78 79 Thus, phorbol esters should produce a stronger downstream response of PKC-dependent pathways than does ischemia. One consequence of exposure of heart tissue to phorbol esters is the activation of the ERK cascade.35 36 59 This PKC-dependent pathway is also used by endothelin-1 and 1-adrenergic agonists to activate the ERK cascade.35 36 80 It is unlikely that activation of p38/RK or JNK/SAPKs is a downstream consequence of PKC activation in the ischemic heart. Phorbol esters at best only modestly activate p38/RK or JNK/SAPKs in cultured ventricular myocytes,28 in HeLa cells,45 or in many other cell types.45 81 82 Analogous experiments in perfused hearts are difficult to interpret because of the vasoconstrictive effects of phorbol esters. We are aware that the modest stimulation of JNK activity by phorbol esters in Jurkat cells or thymocytes can be considerably enhanced by the Ca2+ ionophore, A23187, suggesting synergism between PKC and Ca2+ influx.82 Because of the changes in Ca2+ handling that occur in ischemia and ischemia/reperfusion,2 this observation may be relevant to the activation of JNK/SAPKs in our perfused hearts.
The finding that brief periods of ischemia may protect the heart against subsequent ischemic episodes (ischemic preconditioning)8 9 has led to a number of studies addressing the involvement of protein kinases (particularly PKC) in this phenomenon.9 A role for PKC in mediating the protective effects of ischemic preconditioning has been suggested from the use of phorbol esters and protein kinase inhibitors such as staurosporine, polymyxin, calphostin C, and chelerythrine. Phorbol esters precondition the heart, whereas protein kinase inhibitors prevent this in a number of model systems.83 84 85 86 Equally, known physiological activators of PKC in the heart (1-adrenergic agonists,78 79 endothelin-1,79 and bradykinin87 ) also induce preconditioning.88 89 90 91 Others have failed to prevent ischemic preconditioning with protein kinase inhibitors such as polymyxin B and H-7.92 The role of PKC in preconditioning therefore remains controversial. The differences reported for the importance of PKC may be species or model dependent.86 92 We speculate that the stress-activated MAPK pathways act in parallel or in addition to PKC to mediate the preconditioning effects of ischemia. One possible mechanism for protection by p38/RK may involve the phosphorylation of small HSPs by MAPKAPK2.47 It is not yet known whether the small HSPs are cardioprotective in the same way as are the large HSPs.93 94 Thus, future studies to assess the role of stress-activated MAPKs in the ischemic heart should entail the use of specific MAPK cascade inhibitors, such as SB20358095 and PD098059.96
We have also shown that transfection of ventricular myocytes with constitutively activated MEKK1 and SEK1 induces some of the features of the hypertrophic adaptation (Fig 4). The protein kinase MEKK1 was originally identified as a potential upstream activator of MEK when overexpressed in COS cells.50 Because MEKK1 was highly homologous to the yeast protein kinases Byr2 and Ste11 (from Schizosaccharomyces pombe and Saccharomyces cerevisiae, respectively), it was suggested that MEKK1 might be the mammalian equivalent of these MAPK kinase kinases and provide an important link between G protein–coupled receptors and the ERK pathway.50 Recent work has shown that although MEKK1 overexpression may lead to activation of MEK, it at best only minimally activates ERKs.97 Thus, there exists a MEKK1SEK1JNK/SAPK cascade51 52 that is analogous to the c-RafMEKERK cascade.12 15 The activation of the JNK/SAPK cascade by MEKK1 is now considered to be a more relevant downstream event than the activation of the ERK cascade,51 52 and it has been suggested that MEKK1 is a SEK1 kinase.52 The highest levels of expression of MEKK1 mRNA are in the heart and spleen,50 and MEKK1 has been cloned from murine heart.42 Thus, activation of MEKK1 may have important consequences in the ventricular myocyte. However, we do not know that MEKK1 protein is present in the heart.
We must emphasize that we do not know whether MEKKs (or other JNK kinase kinases) or JNK kinases/SEKs are activated by ischemia/reperfusion. The recombinant proteins required for their assay are not readily available. We do not know of any reports in which MEKK activity has been assayed, and we know of only one report in which activities of JNK kinases/SEKs have been assayed.98 Equally, we cannot exclude the possibility that some of the effects of transfection of MEKK1 are mediated through the ERK cascade rather than through the JNK/SAPK cascade. Further MEKK species have recently been identified (MEKK2 and MEKK3), and overexpression of these leads to activation of both the ERK and JNK/SAPK cascades.99 Furthermore, there is no evidence that MEKK is the MAPK kinases kinase for the p38/RK cascade. This is important because this cascade can be activated independently of the JNK/SAPK cascade (Figs 2 and 3); thus, the mechanisms of activation of the two cascades must be distinct. Our results with transient transfection of N-MEKK1 must be interpreted cautiously.
Although the -helical deletion in -SEK1 construct used in the present study should increase its constitutive activity over the wild-type enzyme, -SEK1 did not activate ANF promoter activity (Fig 4, middle left). This is similar to the minimal effect (twofold increase) of partially activated MEK1 on ANF promoter activity.38 By analogy with MEK1,100 the low level of ANF promoter activation may reflect the relatively limited activation of MEK induced by the activating mutation compared with the stimulation induced by the physiological phosphorylation. In other words, the activity of -SEK1 is closer to (but greater than) the activity of the unphosphorylated wild-type enzyme rather than the fully active, fully phosphorylated species. As shown in Fig 4, middle left, ANF promoter activity was synergistically stimulated by cotransfection of N-MEKK1 with -SEK1. One explanation may be that the expressed -SEK1 can now be further activated by a N-MEKK1–mediated phosphorylation. Thus, MEKK1 and SEK1 may exist on a common pathway so that N-MEKK1 may use the cotransfected -SEK1 for signaling. These experiments are not unequivocal, because there may be cross talk between the ERK and the JNK/SAPK cascades, and we cannot exclude the possibility that ERK may be mediating some of the effects of N-MEKK1. It is not possible to investigate whether N-MEKK1 activates ERK in cardiac myocytes (even when epitope-tagged ERK is cotransfected) because of the low efficiencies of transfection (2%) in these cells. Equally, we cannot assess the contribution of endogenous SEK1 (as opposed to MEK) in the activation of the ANF promoter by N-MEKK1 (Fig 4, middle left). Indeed, the twofold activation of the ANF promoter by cotransfection of N-MEKK1+-SEK1 compared with N-MEKK1 alone (Fig 4, middle left) suggests that the influence of SEK1 may be rather weak.
The preceding discussion has assumed that activation of stress-activated MAPK cascades is largely beneficial. It is still not clear whether activation of MEKK and/or the stress-activated MAPKs increases or diminishes cell survival. Recent reports have suggested that activation of MEKK and JNK/SAPKs may be involved in the processes leading to cell death.101 102 103 The processes involved are not entirely clear, and on the basis of experiments with dominant-negative JNK/SAPK constructs, the effects of MEKK may be independent of its ability to activate JNK/SAPKs.103 Our results must be considered with these points borne in mind.
The JNK/SAPKs may also play an important role in the response to ischemia/reperfusion in other tissues (eg, the proliferative/hypertrophic response of renal tubular epithelium to ischemic injury). Ischemia/reperfusion activates JNK/SAPKs in rat kidneys.104 Such kidneys also display enhanced binding of c-Jun and ATF2 (both substrates for JNK/SAPKs22 23 43 44 ) to AP-1–binding sites and cAMP response elements.105 JNK/SAPKs are also activated in Madin-Darby canine kidney epithelial cells that, after ATP depletion with cyanide and deoxyglucose, are subsequently allowed to undergo ATP repletion.104 The situation is thus very similar to that in the perfused heart (Fig 3).
The p38/RK and JNK/SAPK pathways potentially provide an important signaling link from the extracellular surface of the myocyte to the changes that follow in the nucleus. We have shown here that MEKK can initiate the changes in gene expression and myocyte cell size that are typical of the hypertrophic response. JNK/SAPKs regulate the c-Jun transactivating activity at AP-1 sites,67 and these are present in the promoters of a number of genes, including ANF and vMLC-2.65 Other transcription factors (Elk1 and ATF2) are substrates for p38/RK and the JNK/SAPKs, and their transactivating activity is increased by phosphorylation.42 44 Thus, although the Rasc-RafMEKERK cascade is involved in hypertrophy induced by Gq protein–coupled receptor activation,38 61 62 63 we suggest that two (or more) additional protein kinase cascades may converge to produce a similar phenotype. Indeed, activation at serum response elements, which are recognized by Elk1,106 may be important in the regulation of ANF expression.107 The roles of stress-activated MAPKs in the heart are currently unclear. We would like to suggest that activation of these enzymes during myocardial ischemia and ischemia/reperfusion may be cardioprotective and particularly may induce the reactive hypertrophy and ventricular remodeling that allow maintenance of cardiac output in pathological situations. It may equally represent a response leading to necrosis.
While this manuscript was undergoing editorial review, Knight and Buxton108 reported activation of MAPKs by ischemia/reperfusion (but not by ischemia alone) in the perfused heart. Using a pull-down assay with GST–c-Jun1-79,23 they showed that JNK/SAPK species were activated in a process that depended on the presence of extracellular Ca2+. JNK/SAPK was not activated by H2O2, but its activation by ischemia/reperfusion was prevented by inclusion of both superoxide dismutase and catalase together in the perfusion medium. An MBPK(s) was also activated by ischemia/reperfusion (but not by ischemia alone). This differed from the JNK/SAPK in that its activation was less transient, was Ca2+ independent, and could be induced by H2O2. Activation by ischemia/reperfusion was prevented by enzymes that scavenge reactive oxygen species. Although the specificity of the pull-down assay ensures that ischemia/reperfusion is activating JNK/SAPKs, the identity of the MBPK(s) is unclear, since the only characterization carried out was that it bound to DEAE-Sephacel and was eluted by 0.5 mol/L NaCl.
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This study was supported by grants from The Wellcome Trust, the British Heart Foundation (BHF), and the UK Biotechnology and Biological Sciences Research Council. We thank Nicola Haward for culturing the neonatal ventricular myocytes. Dr Fuller is a BHF Lecturer in Basic Science, Dr Ben-Levy holds a long-term FEBS Fellowship, and Dr Marshall is Cancer Research Campaign Gibb Life Research Fellow.
Received August 16, 1995; accepted May 6, 1996.
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 N. Khandoudi, P. Delerive, I. Berrebi-Bertrand, R. E. Buckingham, B. Staels, and A. Bril Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-{gamma}, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury Diabetes, May 1, 2002; 51(5): 1507 - 1514. [Abstract] [Full Text] [PDF]
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 T. Minamino, T. Yujiri, N. Terada, G. E. Taffet, L. H. Michael, G. L. Johnson, and M. D. Schneider MEKK1 is essential for cardiac hypertrophy and dysfunction induced by Gq PNAS, March 19, 2002; 99(6): 3866 - 3871. [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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P. P. Domingos, P. M. Fonseca, W. Nadruz Jr., and K. G. Franchini Load-induced focal adhesion kinase activation in the myocardium: role of stretch and contractile activity Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H556 - H564. [Abstract] [Full Text] [PDF]
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 B.G. PETRICH, P. LIAO, and Y. WANG Using a Gene-switch Transgenic Approach to Dissect Distinct Roles of MAP Kinases in Heart Failure Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 429 - 438. [Abstract] [PDF]
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X. Zhang, G. Azhar, K. Nagano, and J. Y. Wei Differential vulnerability to oxidative stress in rat cardiac myocytes versus fibroblasts J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2055 - 2062. [Abstract] [Full Text] [PDF]
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N. Degousee, E. Stefanski, T. F. Lindsay, D. A. Ford, R. Shahani, C. A. Andrews, D. J. Thuerauf, C. C. Glembotski, T. J. Nevalainen, J. Tischfield, et al. p38 MAPK Regulates Group IIa Phospholipase A2 Expression in Interleukin-1beta -stimulated Rat Neonatal Cardiomyocytes J. Biol. Chem., November 16, 2001; 276(47): 43842 - 43849. [Abstract] [Full Text] [PDF]
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S. Wei, E. C. Rothstein, L. Fliegel, L. J. Dell'Italia, and P. A. Lucchesi Differential MAP kinase activation and Na+/H+ exchanger phosphorylation by H2O2 in rat cardiac myocytes Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1542 - C1550. [Abstract] [Full Text] [PDF]
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 I.-K. S. Aggeli, C. Gaitanaki, A. Lazou, and I. Beis Stimulation of multiple MAPK pathways by mechanical overload in the perfused amphibian heart Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1689 - R1698. [Abstract] [Full Text] [PDF]
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R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
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Y. Yue, M. Krenz, M. V. Cohen, J. M. Downey, and S. D. Critz Menadione mimics the infarct-limiting effect of preconditioning in isolated rat hearts Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H590 - H595. [Abstract] [Full Text] [PDF]
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E. G. Araujo, C. Bianchi, K. Sato, R. Faro, X. A. Li, and F. W. Sellke Inactivation of the MEK/ERK pathway in the myocardium during cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., April 1, 2001; 121(4): 773 - 781. [Abstract] [Full Text] [PDF]
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G. Vassort Adenosine 5'-Triphosphate: a P2-Purinergic Agonist in the Myocardium Physiol Rev, April 1, 2001; 81(2): 767 - 806. [Abstract] [Full Text] [PDF]
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J. M. Kyriakis and J. Avruch Mammalian Mitogen-Activated Protein Kinase Signal Transduction Pathways Activated by Stress and Inflammation Physiol Rev, April 1, 2001; 81(2): 807 - 869. [Abstract] [Full Text] [PDF]
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 D. Hreniuk, M. Garay, W. Gaarde, B. P. Monia, R. A. McKay, and C. L. Cioffi Inhibition of C-Jun N-Terminal Kinase 1, but Not c-Jun N-Terminal Kinase 2, Suppresses Apoptosis Induced by Ischemia/Reoxygenation in Rat Cardiac Myocytes Mol. Pharmacol., April 1, 2001; 59(4): 867 - 874. [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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C. Beauloye, L. Bertrand, U. Krause, A.-S. Marsin, T. Dresselaers, F. Vanstapel, J.-L. Vanoverschelde, and L. Hue No-Flow Ischemia Inhibits Insulin Signaling in Heart by Decreasing Intracellular pH Circ. Res., March 16, 2001; 88(5): 513 - 519. [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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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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O. F. Bueno, L. J. De Windt, H. W. Lim, K. M. Tymitz, S. A. Witt, T. R. Kimball, and J. D. Molkentin The Dual-Specificity Phosphatase MKP-1 Limits the Cardiac Hypertrophic Response In Vitro and In Vivo Circ. Res., January 19, 2001; 88(1): 88 - 96. [Abstract] [Full Text] [PDF]
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 S. Tinton and P. B. Calderon Role of Protein Phosphorylation in the Inhibition of Protein Synthesis Caused by Hypoxia in Rat Hepatocytes International Journal of Toxicology, January 1, 2001; 20(1): 21 - 27. [Abstract] [PDF]
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S. Ghosh, L. L Ng, S. Talwar, I. B Squire, and M. Galinanes Cardiotrophin-1 protects the human myocardium from ischemic injury: Comparison with the first and second window of protection by ischemic preconditioning Cardiovasc Res, December 1, 2000; 48(3): 440 - 447. [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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S. Okubo, N. L. Bernardo, G. T. Elliott, M. L. Hess, and R. C. Kukreja Tyrosine kinase signaling in action potential shortening and expression of HSP72 in late preconditioning Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2269 - H2276. [Abstract] [Full Text] [PDF]
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M. Sato, G. A. Cordis, N. Maulik, and D. K. Das SAPKs regulation of ischemic preconditioning Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H901 - H907. [Abstract] [Full Text] [PDF]
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M. Behrends, R. Schulz, H. Post, A. Alexandrov, S. Belosjorow, M. C. Michel, and G. Heusch Inconsistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1111 - H1119. [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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A. Dana, M. Skarli, J. Papakrivopoulou, and D. M. Yellon Adenosine A1 Receptor Induced Delayed Preconditioning in Rabbits : Induction of p38 Mitogen-Activated Protein Kinase Activation and Hsp27 Phosphorylation via a Tyrosine Kinase- and Protein Kinase C-Dependent Mechanism Circ. Res., May 12, 2000; 86(9): 989 - 997. [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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Y. J. Kang, Z.-X. Zhou, G.-W. Wang, A. Buridi, and J. B. Klein Suppression by Metallothionein of Doxorubicin-induced Cardiomyocyte Apoptosis through Inhibition of p38 Mitogen-activated Protein Kinases J. Biol. Chem., April 28, 2000; 275(18): 13690 - 13698. [Abstract] [Full Text] [PDF]
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H. Tong, W. Chen, R. E. London, E. Murphy, and C. Steenbergen Preconditioning Enhanced Glucose Uptake Is Mediated by p38 MAP Kinase Not by Phosphatidylinositol 3-Kinase J. Biol. Chem., April 14, 2000; 275(16): 11981 - 11986. [Abstract] [Full Text] [PDF]
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L. Faccio, A. Chen, C. Fusco, S. Martinotti, J. V. Bonventre, and A. S. Zervos Mxi2, a splice variant of p38 stress-activated kinase, is a distal nephron protein regulated with kidney ischemia Am J Physiol Cell Physiol, April 1, 2000; 278(4): C781 - C790. [Abstract] [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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A. Nakano, C. P. Baines, S. O. Kim, S. L. Pelech, J. M. Downey, M. V. Cohen, and S. D. Critz Ischemic Preconditioning Activates MAPKAPK2 in the Isolated Rabbit Heart : Evidence for Involvement of p38 MAPK Circ. Res., February 4, 2000; 86(2): 144 - 151. [Abstract] [Full Text] [PDF]
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O. M. Hernandez, D. J. Discher, N. H. Bishopric, and K. A. Webster Rapid Activation of Neutral Sphingomyelinase by Hypoxia-Reoxygenation of Cardiac Myocytes Circ. Res., February 4, 2000; 86(2): 198 - 204. [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. N. Sack, R. M. Smith, and L. H. Opie Tumor necrosis factor in myocardial hypertrophy and ischaemia -- an anti-apoptotic perspective Cardiovasc Res, February 1, 2000; 45(3): 688 - 695. [Full Text] [PDF]
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C. E. Ganote and S. C. Armstrong Adenosine and preconditioning in the rat heart Cardiovasc Res, January 1, 2000; 45(1): 134 - 140. [Full Text] [PDF]
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Y. Takeishi, J.-i. Abe, J.-D. Lee, H. Kawakatsu, R. A. Walsh, and B. C. Berk Differential Regulation of p90 Ribosomal S6 Kinase and Big Mitogen-Activated Protein Kinase 1 by Ischemia/Reperfusion and Oxidative Stress in Perfused Guinea Pig Hearts Circ. Res., December 3, 1999; 85(12): 1164 - 1172. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, S. Huang, X. Cao, X.-L. Tang, R. C. X. Li, Y.-T. Zheng, Y. Qiu, A. Clerk, P. Sugden, et al. PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1771 - H1785. [Abstract] [Full Text] [PDF]
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