Published online before print September 27, 2001, doi: 10.1161/hh2201.099434
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© 2001 American Heart Association, Inc.
Cellular Biology |
Differential Activation of Mitogen-Activated Protein Kinase Cascades and Apoptosis by Protein Kinase C 
and 
in Neonatal Rat Ventricular Myocytes
From the Cardiovascular Institute, Loyola University Chicago, Maywood, Ill.
Correspondences to Maria C. Heidkamp, PhD, Loyola University Medical Center, 2160 South First Ave, Maywood, IL 60153. E-mail mheidka{at}lumc.edu
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Abstract |
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Abstract—— Protein kinase C (PKC)
and PKC
translocation in neonatal rat ventricular myocytes (NRVMs) is accompanied by subsequent activation of the ERK, JNK, and p38MAPK cascades; however, it is not known if either or both novel PKCs are necessary for their downstream activation. Use of PKC inhibitors to answer this question is complicated by a lack of isoenzyme specificity, and the fact that many PKC inhibitors stimulate JNK and p38MAPK activity. Therefore, replication-defective adenoviruses (Advs) encoding constitutively active (ca) mutants of PKC and PKC were used to test if either or both of these PKCs are sufficient to activate ERKs, JNKs, and/or p38MAPK in NRVMs. Adv-caPKC infection (1 to 25 multiplicities of viral infection (MOI); 4 to 48 hours) increased total PKC levels in a time- and dose-dependent manner, with maximal expression observed 8 hours after Adv infection. Adv-caPKC induced a time- and dose-dependent increase in phosphorylated p42 and p44 ERKs, as compared with a control Adv encoding ß-galactosidase (Adv-neßgal). Maximal ERK phosphorylation occurred 8 hours after Adv infection. In contrast, JNK was only minimally activated, and p38MAPK was relatively unaffected. Adv-caPKC infection (1 to 25 MOI, 4 to 48 hours) increased total PKC levels in a similar fashion. Adv-caPKC (5 MOI) induced a 29-fold increase in phosphorylated p54 JNK, and a 15-fold increase in phosphorylated p38MAPK 24 hours after Adv infection. In contrast, p42 and p44 ERK were only minimally activated. Whereas neither Adv induced NRVM hypertrophy, Adv-caPKC, but not Adv-caPKC, induced NRVM apoptosis. We conclude that the novel PKCs differentially regulate MAPK cascades and apoptosis in an isoenzyme-specific and time-dependent manner.
Key Words: signal transduction • cardiomyocyte • hypertrophy • adenovirus
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There is now substantial evidence to indicate a critical role for protein kinase C (PKC) activation in coordinating specific aspects of cardiomyocyte hypertrophy.1 Previous studies have also implicated PKCs as potential upstream regulators of the mitogen-activated protein kinases (MAPK), which are involved in both hypertrophic signal transduction,2 as well as apoptosis.3 However, cardiomyocytes express several PKC isoenzymes that are differentially activated by various stimuli. For instance, the hypertrophic agonists endothelin-1 (ET) and phenylephrine (PE) caused the membrane translocation of PKC
, and to a lesser extent PKC, in cultured neonatal rat ventricular myocytes (NRVMs).4,5 ET-induced PKC and PKC translocation was accompanied by subsequent activation of all three MAPK cascades.5–9 In contrast, electrical stimulation of contraction induced a similar degree of cardiomyocyte hypertrophy, but predominantly activated PKC rather than PKC.10 Electrical pacing was also associated with a rapid increase in JNK10,11 and p38MAPK12 activities, but ERKs were not significantly activated.10,11 None of these hypertrophic stimuli induced the membrane translocation of PKC
, the major Ca2+-dependent, phorbol-ester–sensitive PKC in NRVMs.4,5,10 Although PKC has been implicated in the downstream activation of both ERKs and JNKs during ischemic preconditioning,13,14 it is currently not known which, if either PKC isoenzyme is responsible for activating specific MAPK cascades during cardiomyocyte hypertrophy.15 Furthermore, it is not known whether PKC or PKC plays a role in the downstream activation of MAPKs during cardiomyocyte apoptosis.
One approach to answer these questions is to use pharmacological inhibitors to block PKC activation, and then test whether one or more PKCs are upstream of each of the three MAPK cascades. However, this approach is problematic due to a lack of isoenzyme selectivity, and the fact that many PKC inhibitors stimulate JNK and p38MAPK cascades even in the absence of exogenous stimuli.10,16–18 Therefore, in this report we make use of replication-defective adenoviruses encoding constitutively active (ca) mutants of PKC and PKC to examine which, if either of these novel PKC isoenzymes, is sufficient to activate ERKs, JNKs, and/or p38MAPK in NRVMs. We also examine whether caPKC or caPKC overexpression is sufficient to induce NRVM hypertrophy or apoptosis.
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Materials and Methods |
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Reagents
Reagents used are listed in the online data supplement available at http://www.circresaha.org
Cell Culture
Animals were handled in accordance with the Guiding Principles in the Care and Use of Animals, approved by the Council of the American Physiological Society. NRVMs were isolated by collagenase digestion, as previously described.19 For further detail, see online data supplement.
Adenoviral Constructs
A replication-defective adenovirus encoding rat caPKC (Adv-caPKC) was constructed as previously described.10 Rat caPKC adenovirus (Adv-caPKC) was constructed by first subcloning caPKC cDNA (kindly provided by Dr Peter Parker, Imperial Cancer Research Fund Laboratories, and Dr Peter Sugden, Imperial College of Science, Technology and Medicine, London, UK) into a pAC-CMV-pLpA-SR plasmid. The enzyme was made constitutively active by a point mutation (A159E) of its inhibitory pseudosubstrate domain.20 The subcloned construct was cotransfected along with pJM17 plasmid that contained adenoviral DNA into HEK293 cells. Following homologous recombination, the adenovirus was plaque-purified and amplified. Cell extracts from Adv-caPKC– and Adv-PKC–infected NRVMs both demonstrated increased PKC activity (assessed by phosphorylation of isoenzyme-selective peptide substrates) in the absence of phorbol myristate acetate (PMA) (data not shown). To control for adenoviral infection, a replication-defective adenovirus for nuclear encoded ß-galactosidase (Adv-neßgal; kindly provided by Dr M.K. Rundell, Northwestern University) was also used. The multiplicity of viral infection (MOI) for each virus was determined by dilution assay in HEK293 cells.
Western Blotting
NRVMs were homogenized in lysis buffer.21 Equal amounts of extracted proteins were separated on 10% SDS-polyacrylamide gels with 5% stacking gels. Proteins were transferred to PVDF membranes, and the Western blots probed with antibodies specific for PKC, PKC, PKC, or the phosphorylated forms of ERKs, JNKs or p38MAPK. Membranes were stripped and reprobed with antibodies recognizing both phosphorylated and unphosphorylated forms of the MAPKs in order to confirm equal loading. Primary antibody binding was detected with horseradish-peroxidase-conjugated goat anti-mouse or goat anti-rabbit secondary antibody and visualized by enhanced chemiluminescence (Amersham, Arlington Heights, IL). Band intensity was quantified by laser densitometry.
MAPK Activity Assays
ERK activity was measured using MAPK IP-Kinase assay kit (UBI), according to manufacturer’s instructions. Following immunoprecipitation of JNKs with anti-JNK mAb, JNK activity was measured using SAPK1a/JNK2 assay kit (UBI).
Cellular Composition
Total cellular protein and DNA content were measured as described previously.22
Detection of Apoptosis
Three different methods were used to detect apoptosis in NRVMs. DNA fragmentation was assayed using the Suicide-Track DNA Ladder Isolation Kit (Oncogene Research Products) according to manufacturer’s instructions. Fragmented DNA was separated from intact, high molecular weight genomic DNA, and the fragments were resolved by agarose gel electrophoresis. Terminal deoxynucleotidyl transferase-mediated dUTP in situ nick-end labeling (TUNEL) was also used to detect apoptotic nuclei by fluorescence microscopy (ApopTag fluorescein in situ apoptosis detection kit; Intergen). Cell nuclei were counterstained with DAPI to aid in visualization. FITC-labeled apoptotic nuclei were imaged with a Zeiss LSM 510 confocal microscope. Thirdly, apoptotic nuclei were imaged using an Hitachi H-600 transmission electron microscope.
Data Analysis
Results were expressed as mean±SEM. Normality was assessed using the Kolmogorov-Smirnov test, and homogeneity of variance was assessed using Levene’s test. Data were compared by 1-way blocked ANOVA or 1-way blocked ANOVA on Ranks, followed by Dunnett’s or Dunn’s test, where appropriate. Data were analyzed using the SigmaStat statistical software package, version 1.0 (Jandel Scientific).
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Results |
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PKC Inhibitors Activate JNK and p38MAPK
Initial experiments were performed to examine whether PKC inhibitors affected that basal phosphorylation state of MAPKs in NRVMs. As seen in Table 1, the nonselective PKC inhibitors chelerythrine and calphostin C reduced basal p44 ERK phosphorylation while substantially increasing JNK and p38MAPK activation. Staurosporine and Ro18220 had less dramatic effects. Even the PKC
-selective inhibitor rottlerin markedly increased p38MAPK phosphorylation 7.4±0.4-fold as compared with untreated cells. Taken together, these observations made it difficult to use these pharmacological agents to ascertain whether one or more PKC isoenzymes are necessary for downstream activation of individual MAPK cascades in response to exogenous stimuli.
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caPKC and caPKC Overexpression
To address whether individual PKCs are sufficient to activate each of the MAPK cascades, we generated replication-defective Adv encoding caPKC and caPKC, and compared expression levels of each protein over time. An Adv encoding ß-galactosidase (Adv-neßgal) was used to control for nonspecific effects of viral infection. As seen in the representative Western blot in Figure 1A, Adv-PKC (5 MOI) induced a marked increase in immunoreactive PKC. Lower and higher concentrations of the virus were also examined, and the results of 4 experiments are summarized in Figures 1B and 1C. As is evident from the figure, the highest Adv concentration tested (25 MOI) resulted in a 31-fold increase in PKC overexpression (as compared with Adv-neßgal infected cells) within 8 hours of viral infection. Interestingly, caPKC overexpression produced a dose-dependent increase in the level of endogenous PKC (Figure 1A), reaching statistical significance with 25 MOI at 24 to 48 hours (Figure 1C). In contrast, caPKC overexpression had no significant effect on the level of endogenous PKC (data not shown).
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Similarly, Adv-caPKC (5 MOI) produced a time- and dose-dependent increase in immunoreactive PKC (Figure 2A). Lower and higher concentrations of the virus were also examined, and the results of 4 experiments are summarized in Figures 2B and 2C. As is evident from the figure, the highest Adv concentration tested (25 MOI) resulted in a 26-fold increase in PKC overexpression within 8 hours. Interestingly, the higher concentrations of Adv-caPKC also produced a statistically significant, initial increase, followed by a profound decrease in the level of endogenous PKC (Figure 2C). As was the case for Adv-caPKC, caPKC overexpression had no significant effect on the level of endogenous PKC (data not shown).
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caPKC Overexpression Activates ERKs
NRVMs were then infected with Adv-caPKC, Adv-caPKC, or Adv-neßgal (5 MOI), and the phosphorylation state of ERKs was examined at multiple time points (4 to 48 hours) after viral infection. As shown in Figure 3A, only Adv-PKC resulted in the activation of p42 and p44 ERK. None of the viruses caused a significant change in the level of total (ie, phosphorylated + nonphosphorylated) p42 and p44 ERK (data not shown). Lower and higher concentrations of each virus were also examined, and the results of 4 experiments are summarized in Figures 3B and 3C. Overexpression of caPKC (Figure 3B) produced a time-dependent increase in phosphorylated ERKs at each of the viral concentrations used (1, 5, and 25 MOI), as compared with Adv-neßgal infected cells. Maximal ERK phosphorylation occurred 8 hours following viral infection (4-fold increase with 5 MOI; 7-fold increase with 25 MOI at 8 hours), which subsequently decreased over time. caPKC overexpression, however, did not result in a significant increase in ERK phosphorylation at any time point with either 1 or 5 MOI of virus, as compared with Adv-ßgal infected cells (Figure 3C). There was a modest increase (
2-fold) in phosphorylated ERKs with 25 MOI of Adv-caPKC, 8 hours after viral infection. These Western blotting results were confirmed by ERK immune complex kinase assays. Adv-caPKC and Adv-caPKC (25 MOI) produced a 20- and 1.6-fold increase, respectively, in ERK activity 8 hours after Adv infection.
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caPKC Overexpression Activates JNKs
NRVMs were then infected with Adv-caPKC, Adv-caPKC, or Adv-neßgal, and JNK phosphorylation was examined at multiple time points (4 to 48 hours) after viral infection. As seen in Figure 4A, Adv-caPKC (5 MOI) induced a marked increase in phosphorylated p46 and p54 JNKs, whereas caPKC had only a minimal effect. None of the Adv had a significant effect on the total levels of p46 and p54 JNK (data not shown). The results of 4 experiments at each viral concentration (1, 5, and 25 MOI) are summarized in Figures 4B and 4C. caPKC overexpression produced a large, time-dependent increase in phosphorylated p54 JNK (Figures 4C) at each viral concentration used, as compared with Adv-ßgal infected cells. Similar increases in the levels of phosphorylated p46 JNK were also observed (data not shown). p54 JNK was maximally activated by Adv-caPKC at 24 hours (29-fold increase with 5 MOI; 47-fold increase with 25 MOI; each at 24 hours), then decreased to basal levels by 48 hours. Overexpression of PKC induced a small, but significant, increase p54 JNK phosphorylation with 5 MOI (4-fold increase at 48 hours) and 25 MOI (6-fold increase at 48 hours). These Western blotting results were confirmed by JNK immune complex kinase assays. Adv-caPKC and Adv-caPKC (25 MOI) produced a 21- and 4-fold increase, respectively, in JNK activity 24 hours after Adv infection.
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caPKC Overexpression Also Activates p38MAPK
Similarly, the effect of overexpressing caPKC and caPKC on the phosphorylation of p38MAPK was examined at the same time points. As shown in the representative Western blot in Figure 5A, Adv-caPKC (5 MOI) induced a marked increase in activated p38MAPK, whereas caPKC overexpression had little effect. None of the viruses significantly affected total levels of p38MAPK (data not shown). The results of 4 experiments at each viral concentration are summarized in Figures 5B and 5C. Overexpressing caPKC produced a time-dependent elevation in activated p38MAPK reaching a 15-fold increase with 5 MOI of virus at 24 hours, as compared with Adv-ßgal infected cells. Although caPKC increased p38MAPK phosphorylation 2 to 4 fold, these differences did not achieve statistical significance. Overall, these data indicate that caPKC was sufficient to activate p38MAPK, and like p46 and p54 JNK, this activation occurred 24 hours after caPKC overexpression.
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caPKC Overexpression Alters Cell Morphology With No Change in Protein/DNA Ratios
NRVMs were infected with Adv-neßgal, Adv-caPKC, or Adv-caPKC, and cellular composition and morphology were analyzed at various time points (8 to 48 hours) after Adv infection (Figure 6). Overexpression of caPKC resulted in cell elongation with no change in protein/DNA ratio, consistent with our previous studies in low-density NRVMs.22 Overexpression of caPKC, however, resulted in cell rounding and detachment beginning 24 hours after adenoviral infection. Although there were no changes in protein/DNA ratio, increasing concentrations of Adv-caPKC produced a dose-dependent decrease in both total protein and DNA content over time, as compared with NRVMs infected with Adv-neßgal (data not shown).
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caPKC Overexpression Results in Apoptosis
To determine whether the caPKC-induced morphological changes and cell detachment were associated with apoptosis, NRVMs were infected with either Adv-neßgal, Adv-caPKC, or Adv-caPKC (25 MOI) and subsequently analyzed for DNA fragmentation. Staurosporine (1 µmol/L, 24 hours) was used as a positive control for apoptosis. Neither Adv-neßgal– nor Adv-caPKC–infected cells exhibited DNA laddering at any of the time points measured. However, NRVMs overexpressing caPKC exhibited the characteristic degradation of DNA into oligonucleosomal-length fragments 24 hours after adenoviral infection (Figure 7A). DNA fragmentation was also confirmed by the TUNEL assay. As seen in Figures 7B through 7E, only Adv-caPKC–infected and staurosporine-treated cells stained positive for apoptotic nuclei. Furthermore, chromatin condensation and margination were apparent by electron microscopy of myocytes overexpressing caPKC and cells treated with staurosporine (Figures 7H and 7I), but not in NRVMs infected with Adv-neß-gal or Adv-caPKC (Figures 7F and 7G).
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Discussion |
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In this report, we provide new evidence that exogenous stimuli which differentially activate PKC isoenzymes can transduce their downstream signals to specific MAPK cascades. These novel results may also help to clarify the critical role of PKCs in modulating both cardiomyocyte hypertrophy and apoptosis.
Our results confirm previous studies that demonstrate that ET activates ERKs, JNKs, and p38MAPK in NRVMs.5–9 In addition, Clerk et al9 have shown, using pharmacological approaches, that ET-induced activation of both ERKs and p38MAPK was dependent on the upstream activation of one or more PMA-sensitive isoenzymes of PKC. These investigators used the PKC inhibitor GF109203X, and downregulation of phorbol-ester–sensitive PKCs with PMA, to block ET-induced PKC activation; however, both pharmacological interventions raised basal p38MAPK phosphorylation. Our results demonstrate that other PKC inhibitors not only activate p38MAPK, but also substantially increase basal p46 and/or p54 JNK phosphorylation. Similarly, Yu et al17 have demonstrated that chelerythrine increased JNK and p38MAPK activities in HeLa cells via an oxidative stress mechanism independent of PKC activation. Therefore, we attempted a more direct and specific approach to investigate which, if any, PKC isoenzyme was sufficient to activate individual MAPKs in NRVMs.
We unexpectedly found a previously unrecognized interdependence between the expression levels of the two novel PKCs in cardiomyocytes. As seen in Figures 1 and 2, caPKC overexpression caused a time- and dose-dependent increase in endogenous PKC, whereas caPKC overexpression substantially reduced endogenous PKC. Neither caPKC affected endogenous PKC levels. The mechanisms responsible for these changes are not known but are clearly important to the interpretation of our subsequent results. For instance, upregulation of endogenous PKC may have been responsible for the modest increase in JNK phosphorylation observed in caPKC-overexpressing cells (Figure 4). Similarly, the significant reduction in endogenous PKC may have contributed in some way to the substantial activation of JNKs and p38MAPK (Figures 4 and 5), as well as the apoptotic response (Figure 7) after Adv-caPKC infection (see below). An additional level of complexity is suggested by the observation that high levels of Adv-caPKC resulted in the rapid and transient activation of p42 ERK (Figure 3C). Although overexpressing caPKC reduced PKC levels by 24 hours, there was an initial, modest increase in PKC levels (Figure 2C), which may explain why p42 ERK phosphorylation was increased at that time point. An alternative explanation for the downstream activation of ERKs by caPKC may be due to the altered expression of isoenzyme-specific receptors for activated C kinase (RACK). Pass et al23 demonstrated that high levels of one PKC isoenzyme not only increased the levels of its specific RACK and the interaction with its receptor, but also led to increased expression and interaction with the RACK of another PKC isotype. This dynamic regulation of RACK expression by specific PKCs may explain the confounding dose-dependent effects of caPKC and caPKC overexpression on activating the various MAPK cascades.
Our evidence indicating that caPKC overexpression induces ERK activation provides additional evidence that PKC is an upstream regulator of the Ras-Raf-MEK-ERK cascade in cardiomyocytes.5,14,15,22,24,25 Ping et al14 have demonstrated that adenovirally mediated overexpression of wildtype PKC increased basal p44, and to a lesser extent p42 ERK, activity in cultured adult rabbit cardiomyocytes. Conversely, we recently showed that overexpression of a dominant-negative mutant of PKC markedly suppressed ET-induced ERK activation in NRVMs.22 Although the mechanisms whereby PKCs signal to the ERK cascade are controversial,4,15,26–29 it seems reasonable to conclude that one of the downstream phosphorylation targets of PKC is a protein involved in the regulation of Ras-GTPase activity. Future experiments analyzing Ras-GTP loading in Adv-caPKC–infected NRVMs are needed to confirm this speculation.
Evidence in support of a direct role for PKCs in JNK activation is contradictory. Bogoyevitch et al7 showed that PMA was only a weak activator of p54 and p46 JNK in low-density NRVMs; however, PMA-induced JNK activation is highly dependent on Ca2+ influx.11,30 Thus it is conceivable that the inability to detect PMA-induced JNK activation was due to the absence of spontaneous [Ca2+]i transients in low-density cultures. Additionally, as PMA activates PKC, PKC, and the Ca2+-dependent isoform PKC in NRVMs,4 their combinatorial effect on JNK activation may be due to differing signals originating from multiple PKC isoenzymes. There is also some evidence for PKC isoenzyme-selective activation of JNKs in cardiomyocytes and other cell types. For instance, we showed that electrical pacing of NRVMs predominantly activated PKC rather than PKC, which was associated with increased JNK phosphorylation.10 In contrast, PKC was necessary for JNK activation during ischemic preconditioning of adult rabbit cardiomyocytes.13,14 In mouse epidermal cells, overexpression of dominant-negative mutants of either PKC or PKC, but not PKC, inhibited UV light–induced activation of both ERKs and JNKs.31 Although these cell-type, species, and developmental differences could account for some of the variability in PKC isoenzyme-dependent JNK activation, our data suggest that PKC is the predominant PKC isoenzyme involved in activating the JNK cascade in NRVMs. It should be pointed out, however, that other PKC-independent signaling pathways must also contribute to maximal JNK activation in these cells.7
Clerk et al16 previously showed that ET-induced p38MAPK activation required a PMA-sensitive PKC isoenzyme. Our results suggest that PKC is that isoenzyme. Similarly, Saurin et al32 showed that transient transfection of an expression plasmid encoding a different caPKC mutant also increased basal p38MAPK phosphorylation. Although there are substantial data implicating both ERKs and JNKs in various aspects of NRVM hypertrophy, the role of p38MAPK is not as well-defined (reviewed in Sugden and Clerk2). One problem is that there are at least two p38MAPK isoenzymes expressed in cardiomyocytes, and ß,33 which have been implicated in the induction of apoptosis and hypertrophy, respectively.34 Our Western blotting technique did not distinguish between the two isoenzymes, so that the functional consequences of PKC-induced p38MAPK activation in this system are at present not clear.
In this regard, it is possible that the activation of the JNK and p38MAPK cascades by caPKC overexpression occurred via an indirect effect, producing a perceived cellular stress leading to activation of the "stress-activated" kinases and the ultimate induction of NRVM apoptosis. The significant delay between caPKC overexpression (at 8 hours; Figure 2), maximal JNK and p38MAPK phosphorylation (at 24 hours; Figures 4 and 5), and evidence of widespread apoptosis (at 24 to 48 hours; Figure 7) suggests that this was indeed the case. One potential mechanism may relate to the time-dependent decrease in endogenous PKC levels in caPKC-overexpressing cells. Loss of a critical, PKC-dependent cell-survival signal in NRVMs could have triggered the apoptotic response, as was the case with the loss of PKC function in COS cells overexpressing an active-site phosphorylation mutant of PKC.35 As is evident from Figure 6 and our previous report,22 neither caPKC nor caPKC overexpression was sufficient to induce NRVM hypertrophy, and only caPKC overexpression was sufficient to induce apoptosis (Figure 7). Of note, PKC activation has been associated with induction of apoptosis in other cell types,36 but to our knowledge, this is the first report to directly implicate PKC in the induction of apoptosis in cardiomyocytes. Clearly, additional studies are needed to define the precise role of each of these signaling kinases in both the hypertrophic and apoptotic response.
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Acknowledgments |
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The authors thank Alan G. Ferguson and Katie Laures for excellent technical assistance. These studies were supported by NIH RO1 grants HL34328 and HL63711, and gifts to the Cardiovascular Institute from the Nalco Foundation and the Ralph and Marian Falk Trust for Medical Research. Dr Bayer was a recipient of an NIH National Research Service Award (F32 HL10313).
Received April 30, 2001; revision received August 17, 2001; accepted September 19, 2001.
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