© 1995 American Heart Association, Inc.
Articles |
Preconditioning of Isolated Rat Heart Is Mediated by Protein Kinase C
From the Department of Surgery, University of Colorado Health Sciences Center, Denver.
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Abstract |
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Abstract Catecholamines have been implicated in the phenomenon of ischemic preconditioning. We have previously demonstrated that ischemic preconditioning against postischemic mechanical dysfunction in the isolated rat heart is mediated by the
1-adrenergic receptor. The purpose of this study was to
delineate the signal transduction of preconditioning distal to the
1-adrenergic receptor. Our results suggest that (1)
transient ischemia and 1-adrenergic receptor–induced
preconditioning is inhibited by protein kinase C (PKC) antagonists, (2)
functional protection against global ischemia/reperfusion injury can be
induced by infusion of diacylglycerol, the second messenger of the
1-adrenergic pathway, and (3) transient ischemia and
1-adrenergic preconditioning are both characterized by
similar translocation of PKC-
to the sarcolemma of myocardium. These
findings suggest that PKC is an effector of preconditioning in the
isolated rat heart.
Key Words: protein kinase C isoforms • 1-adrenergic receptors • ischemic preconditioning • isolated heart • ischemia/reperfusion
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Brief periods of myocardial ischemia trigger an adaptive response that protects the heart against injury from a subsequent prolonged period of ischemia and reperfusion (IR). This phenomenon, known as ischemic preconditioning,1 2 has been demonstrated to be effective against reperfusion-associated arrhythmias as well as reversible and irreversible ischemic myocardial injury in different models.2 3 Recent investigations have focused attention on potential intrinsic mechanisms of preconditioning4 5 6 7 and searched for benign pharmacological approaches to induce the preconditioned state.7 8 9
We have recently demonstrated7 that ischemic
preconditioning in the isolated rat heart is mediated by stimulated
release of norepinephrine. On the basis of selective
1-adrenergic receptor blockade and stimulation
experiments, we have concluded that preconditioning enhances
postischemic ventricular function of rat heart through an
1-adrenergic mechanism. Reports from other laboratories
support a role for norepinephrine in the mediation of preconditioning
against infarction in both rabbit10 11 12 and dog
hearts.9
Further delineation of the mechanism of preconditioning requires
exploration of the effectors transducing the
1-adrenergic signal. Activation of
1-adrenergic receptors stimulates phosphoinositide
metabolism, producing transient increases in
inositol-1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol
(DAG) levels.13 14 DAG is the primary physiological
activator of protein kinase C (PKC), a ubiquitous Ser-Thr kinase with
multiple isoforms that are associated with a variety of receptors and
physiological effects.15 PKC activation by
1-adrenergic agonists has been demonstrated in numerous
tissues,15 including myocardium.13 14 16 17 18 19 A
recent report suggests that PKC activators protect against infarction
in rabbits.20 DAG-activated PKC translocates to discrete
intracellular compartments transiently. Phosphorylation of selected
targets exerts regulatory effects on numerous functions, including
contraction, metabolism, and protein synthesis.13 14
Therefore, we hypothesized that the mechanism of functional protection
induced by preconditioning in the isolated rat heart involves the
activation of PKC.
In the present study, we tested this hypothesis by determining
whether (1) PKC inhibition could attenuate preconditioning induced by
both transient ischemia and 1-adrenergic
receptor–selective phenylephrine pretreatment, (2) PKC stimulation by
exogenous infusion of DAG could simulate preconditioning, and (3)
translocation of PKC is induced by transient ischemia and
phenylephrine. Our results support the involvement of PKC in
the mechanism of preconditioning in the isolated rat heart.
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Materials and Methods |
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Animals and Materials
Male Sprague-Dawley rats (325 to 350 g, Sasco Inc, Omaha, Neb) were fed a standard diet and acclimated in a quiet quarantine room for 2 weeks before experimentation. The animal protocol was reviewed and approved by the Animal Care and Research Committee, University of Colorado Health Sciences Center. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication No. 85-23, revised 1985). Chelerythrine chloride was obtained from LC Services. Staurosporine, 1-stearoyl-2-arachidonoyl glycerol (SAG), mouse monoclonal sarcomeric anti–
-actin antibody (clone 5C5), and Hoechst No. 33342
(bis-benzamidine) were from Sigma Chemical Co. Albumin (Plasbumin-25,
25%) and OCT compound were from Miles Laboratories. 2-Methylbutane was
from Fisher Scientific. Sheep fluorescein isothiocyanate
(FITC)-conjugated anti-mouse IgG antibody was from Amersham. Rabbit
polyclonal isoform–specific anti-PKC antibodies were from Research and
Diagnostic Antibodies. These antibodies were raised by using
isoform-unique peptide sequences (, 664 to 672; ß1,
661 to 671; ß2, 660 to 673; 
, 681 to 689; , 662 to
673; 
, 728 to 737; 
, 480 to 492; and 
, 673 to 680).
Cy-3–conjugated anti-rabbit IgG antibody was from Jackson
Immunoresearch.
Perfusion of Isolated Rat Heart
The isolated crystalloid-perfused rat heart used in our
laboratory has previously been described.7 21 Rats were
anesthetized (sodium pentobarbital, 60 mg/kg IP) and heparinized (500 U
IP). Hearts were excised, immediately arrested in iced oxygenated
perfusate, mounted, and perfused on a modified Langendorff apparatus at
a constant pressure of 70 mm Hg with Krebs-Henseleit solution (mmol/L:
glucose 5, Ca2+ 1.2, KCl 4.7, and NaHCO3 25.0)
in the nonrecirculating retrograde mode. The time from excision to
perfusion was 
60 to 80 seconds. The perfusate was saturated with a
gas mixture of 92.5% O2/7.5% CO2, achieving a
PO2 of 440 to 460 mm Hg,
PCO2 of 39 to 41 mm Hg, and pH of 7.39 to 7.41
(ABL-4 blood gas analyzer, Radiometer). A water-filled latex balloon
was inserted into the left ventricle through a left atriotomy, and the
volume was adjusted to achieve a stable left ventricular
end-diastolic pressure of 5 to 6 mm Hg during initial
equilibration. Thereafter, the balloon volume was not changed. Pacing
wires were fixed to the right atrium, and hearts were paced at 350
except during transient and sustained ischemia. Pacing was reinitiated
only after 3 minutes of reperfusion in all groups. The index of
myocardial function was left ventricular developed pressure (LVDP, in
millimeters of mercury), which was continuously recorded with a
direct-pressure amplifier (model RS-3200, Gould Electronics) and later
with a computerized bridge amplifier/digitizer (Maclab 8, AD
Instruments) and a Macintosh Quadra 800 minicomputer (Apple Computer).
Hearts that could not initially produce 90 to 120 mm Hg LVDP when
paced at 350 beats per minute were discarded. A three-way stopcock
above the aortic root was turned to create global ischemia, during
which time the heart was placed in a degassed perfusate-filled organ
bath maintained at 37.5°C.
Drug Infusions
All agents were delivered into an infusion port directly above
the aortic cannula (not circulated) at 0.068 mL/min (except when noted)
by a Harvard infusion pump. Phenylephrine and chelerythrine chloride
were dissolved in phosphate-buffered saline (PBS). Staurosporine was
dissolved in dimethyl sulfoxide (DMSO) and diluted with PBS. The
maximal coronary concentration of DMSO was 0.007%. SAG was
dissolved in DMSO at a concentration of 51.7 mmol/L and then diluted
with Plasbumin-25 followed by PBS to final preinfusion concentrations
of 4.4 mmol/L SAG, 11.8% albumin, and 8.8% DMSO. SAG infusions were
delivered at 0.136 mL/min, achieving maximal estimated coronary
concentrations of 0.8% albumin and 0.06% DMSO. We have previously
found that similar coronary concentrations of DMSO have no effect on
developed pressure or recovery from IR (unpublished data). Vehicle
control containing no SAG was prepared and infused similarly.
Experimental Design of Preconditioning Experiments
Preconditioning experiments were conducted as previously
described.7 All hearts were perfused a total of 80
minutes, consisting of a 20-minute preischemic period followed by a
standardized IR challenge: 20 minutes of global ischemia (37.5°C) and
40 minutes of reperfusion. In all, 10 groups of hearts were studied:
control hearts (control group); hearts stimulated by transient ischemia
(TI group), phenylephrine (PE group), and SAG (SAG group); control
hearts treated with blockers (staurosporine [St group] and
chelerythrine [Ch group]); and stimulated hearts cotreated with
blockers (St+TI, St+PE, Ch+TI, and Ch+PE groups). These groups differed
only in the treatment administered during the initial 20-minute
preischemic period. Table 1
outlines the treatment of
all IR experiments. Hearts were not paced during transient and
sustained ischemia. In all experiments, pacing following sustained
ischemia was reinitiated after 3 minutes of reperfusion.
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Immunofluorescence Microscopy
Subcellular localization and translocation studies of PKC
isoforms in hearts after transient ischemia and phenylephrine
stimulation were performed by immunofluorescence staining and were
compared with control hearts. In these experiments, hearts were
harvested and perfused as described above. Five hearts from each group
(control, TI, and PE; 10 to 15 sections per heart) were examined.
Specimens were obtained at the end of phenylephrine infusion and at the
end of transient ischemia. Control specimens were harvested after 10
minutes of equilibration. Ventricular tissue was excised from beating
isolated hearts, blotted, embedded in OCT compound, rapidly frozen in
dry ice–cooled 2-methylbutane, and stored at -70°C until use.
Transverse 5-µm cryosections were prepared with a cryostat (2800
Frigocut E, Reichert-Jung) and collected on
poly-L-lysine–coated slides. All sections were fixed for
10 minutes in a 70% acetone–30% methanol mixture at -20°C. Normal
goat serum (10% in PBS) was applied as a blocking agent and briefly
rinsed with PBS. Sections from each experimental group were then
incubated for 1 hour with diluted primary antibodies (ie, rabbit
polyclonal antibody against PKC isoenzymes) at room temperature with or
without mouse anti–sarcomeric -actin antibody. For all groups,
individual PKC isoform staining was performed on adjacent sections.
After the sections were washed with PBS three times (3 minutes each),
they were incubated with Cy-3–conjugated goat anti-rabbit IgG for 1
hour. During this step, sections also exposed to anti–sarcomeric
-actin antibody were coincubated with FITC-conjugated sheep
anti-mouse IgG. Sections were then washed three times (3 minutes each)
with PBS, followed once for 3 minutes with 0.1% Triton X-100 in PBS.
Nuclei were then stained with bis-benzamidine (10 mg/mL in PBS) for 30
seconds and washed with PBS three times (2 minutes each). Slides were
mounted with a glycerol-based antiquenching media
(o-phenylenediamine HCl) and stored at 4°C.
To test for nonspecific fluorescence, adjacent sections of each experimental group were incubated with nonimmune purified rabbit IgG instead of primary antibodies. Specificity of the staining by the PKC antibodies was determined by preabsorption of the antibodies (1:100) with the immunizing peptides (0.1 mg) for 2 hours at 4°C. Sections were viewed and photographed with a microscope equipped with fluorescence optics (Axioskop with MC-100 camera, Zeiss).
Statistical Analysis
All reported values are mean±SEM. Differences at the 95%
confidence level were considered significant. LVDP and left ventricular
end-diastolic pressure (LVEDP), at corresponding time
points among groups, and functional recoveries were compared by
factorial ANOVA (STATVIEW 4.0, Abacus Concepts). All groups
were analyzed simultaneously with post hoc testing by the
Bonferroni/Dunn procedure.
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Results |
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Functional Preconditioning
The time course of ventricular function in the control, TI, and PE groups is depicted in Fig 1
. The preconditioning
protocol used was previously optimized in our laboratory.7
Although not statistically different, the PE group had a slightly
higher equilibration (LVDP) compared with control and TI hearts. In the
TI group, the expected depression of LVDP after 2 minutes of transient
ischemia rapidly recovered to the equilibration level before sustained
ischemia. In TI and PE hearts, recovery of ventricular function after
sustained ischemia was markedly enhanced compared with control hearts.
The enhancement was apparent within 10 minutes of reperfusion and
persisted throughout reperfusion. Maximal recovered LVDP for TI and PE
hearts was attained within 30 minutes of reperfusion, reaching a
plateau thereafter. In contrast to TI and PE hearts, control hearts
continued to recover function throughout reperfusion, but the rate of
recovery stabilized during the last 10 minutes of reperfusion. The
figures report the function in pressure units (millimeters of mercury),
but the recovered LVDP as a function of the initial equilibration LVDP
(percent LVDP recovered) for each heart was also calculated (Table 2). At the end of reperfusion, recovered LVDP was
48.0±2.6% for control hearts versus 83.2±1.5% for TI hearts
(P<.01) and 80.7±3.1% for PE hearts (P<.01).
Pretreatment with transient ischemia and phenylephrine improved LVEDP
(at constant volume load) during postischemic recovery. Table 2
summarizes the functional recovery and recovery of LVEDP for all IR
experiments. At the end of reperfusion, LVEDP in the control group was
40.8±3.5 mm Hg versus 19.3±1.6 mm Hg (P<.01) and
26.5±1.8 mm Hg (P=.02) in the TI and PE groups,
respectively. These data confirm our previous
observations.7
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Blockade of Preconditioning by PKC Inhibition
To relate PKC activation to the mechanism of preconditioning,
experiments were conducted with the very potent but nonspecific PKC
inhibitor staurosporine.22 Preliminary experiments
indicated that staurosporine infused at 2 nmol/min (coronary
concentration, 100 nmol/L) had negative inotropic effects (data not
shown), whereas no cardiodynamic depression was present at 0.2
nmol/min (10 nmol/L), a dose comparable to that used in a recent
similar study.23 During preischemia, staurosporine did not
affect the recovery of function after transient ischemia in the St+TI
group. Similarly, the maximal inotropic effect of phenylephrine in the
presence of staurosporine (St+PE group) was similar to the effect
of phenylephrine alone (PE group). However, the inotropic effect
decayed to baseline more rapidly in the presence of staurosporine, a
result consistent with the blockade of 1-associated slow
Ca2+ channel potentiation by PKC.24 Fig 2 demonstrates that staurosporine alone had no effect on
either the final recovered LVDP (St group, 41.0±3.6%; control group,
48.0±2.6%) or the LVEDP after IR (St group, 41.5±3.8 mm Hg; control
group, 40.8±3.5 mm Hg) yet eliminated the protection afforded by
pretreatment with transient ischemia (St+TI group, 44.8±3.7%
[P<.01 versus TI group]) and phenylephrine (St+PE
group, 48.6±3.5% [P<.01 versus PE group]).
Additionally, the improvement in LVEDP at end reperfusion observed with
transient ischemia and phenylephrine was retarded with staurosporine
cotreatment (St+TI group, 39.2±2.7 mm Hg [P=.01 versus TI
group]; St+PE group, 39.0±1.5 mm Hg [P=.06 versus PE
group]).
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Although widely used as a PKC inhibitor, staurosporine is a
nonselective kinase inhibitor22 with significant effects
on cAMP-dependent kinase, myosin light chain kinase, and p60v-src
tyrosine kinase. Therefore, experiments were conducted using
chelerythrine, a highly specific PKC inhibitor.25 Unlike
calphostin C (another PKC-specific inhibitor), chelerythrine is water
soluble and does not require UV light activation. Long infusions (ie, 7
minutes) of this agent in the micromolar range were not well tolerated
(excessive ectopy); therefore, infusions were limited to 1 minute at
0.8 µmol/min. Compared with phenylephrine infusion alone, the
infusion of chelerythrine immediately before phenylephrine (ie, Ch+PE
group) prompted a more rapid return to baseline LVDP after
phenylephrine infusion, an effect not observed with 1/50th dose.
Chelerythrine alone did not affect recovered function after IR
(54.5±3.3%) compared with the control condition. Fig 3
demonstrates that chelerythrine blocked functional protection in the
Ch+PE group (recovered LVDP, 53±5.6% [P<.01 versus PE
group]). Preliminary experiments revealed that a similar short
infusion of chelerythrine before transient ischemia failed to eliminate
preconditioning. Previously, elevated norepinephrine concentrations in
coronary effluent were found after transient ischemia in the same
model.7 Therefore, we reasoned that receptor stimulation
may be maximal in the first moments after transient ischemia and that
brief preinfusion of chelerythrine might have washed out before
adequate blockade was established. To examine this possibility,
chelerythrine was infused immediately after transient ischemia.
Chelerythrine also attenuated preconditioning with transient ischemia
(Ch+TI group; recovered DP, 44.5±5.1% [P<.01 versus TI
group]) (Fig 3). End-reperfusion LVEDP for the Ch+TI group was
41.3±3.9 mm Hg (P<.01 versus TI group) and 42.0±3.8
mm Hg for the Ch+PE group (P<.01 versus PE group).
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Simulation of Preconditioning by DAG
Mammalian membranes are rich with inositol phospholipids having
1-stearoyl-2-arachidonoyl substituents. The DAG formed from these
phospholipids (SAG) is a potent PKC activator.15 To
determine if a physiological activator of PKC could simulate transient
ischemic preconditioning, SAG infusion was substituted for transient
ischemia. In similar models, DAG infusions have demonstrated negative
inotropic effects.26 Preliminary experiments demonstrated
that low micromolar SAG concentrations exhibited mild negative
inotropic effects. SAG delivered at 1.2 µmol/min (coronary
concentration, 30 µmol/L) decreased baseline LVDP from 102±3.5 to
92±2.2 mm Hg at the end of infusion (see Fig 4). LVDP
then rapidly returned to baseline. Higher doses could not be delivered
without increasing solvent (DMSO) concentrations to protective levels.
Fig 4 also demonstrates that SAG pretreatment preserved function after
IR (recovered LVDP, 75.0±3% [P<.01 versus control and
vehicle-treated hearts]). Recovery and inotropic effects of the
vehicle-treated control hearts were not different from control hearts.
As with the TI and PE groups, post-IR relaxation of LVEDP with SAG
pretreatment was improved (SAG group, 26.5±4.2 mm Hg
[P=.02 versus control group, P=.01 versus
vehicle-treated group]).
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Translocation of PKC With Transient Ischemia and Phenylephrine
Translocation of PKC activity from cytosolic to particulate
compartments is commonly used as an index of PKC activation. In
isolated neonatal cardiac myocytes, other investigators have
demonstrated that 1-adrenergic stimulation causes rapid
but transient PKC translocation.27 We used indirect
immunofluorescent microscopy to verify the expected translocation of
PKC. Although this technique primarily provides only qualitative data,
the use of isoform-specific anti-PKC antibodies allows the assessment
of both isoform-selective activation and
compartmentation.28 In addition, nuclear staining and
actin staining provided improved subcellular localization and cell-type
identification. Fig 5 demonstrates that the
Ca2+-independent PKC (nPKC) isoforms PKC- and PKC-
translocate with transient ischemic stimulation. Interestingly, PKC-
translocated to the sarcolemma, whereas PKC- translocated mostly
into cardiac myocyte nuclei. Similarly, phenylephrine stimulation also
translocated PKC- to the sarcolemma. In contrast with transient
ischemia, direct 1-adrenergic receptor stimulation with
phenylephrine did not mobilize perinuclear PKC- but sporadically
translocated another nPKC isoform, PKC-, into cardiac myocyte nuclei
(50% of cells examined). Of the classic PKC (cPKC) isoforms,
PKC- (in coronary smooth muscle cells) and PKC-ßI were detected by
the respective antibodies, but these did not show compelling evidence
of translocation with transient ischemia or phenylephrine treatment.
Another novel Ca2+-independent nPKC isoform, PKC-, was
also detected but again did not appear to translocate uniformly. PKC
antibodies preabsorbed with the respective immunizing peptides did not
demonstrate staining. Thus, these results demonstrate activation of PKC
with both transient ischemia and phenylephrine stimulation and suggest
that the PKC- isoform may be involved in preconditioning.
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Discussion |
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In the present study, we further develop the hypothesis that the cardioprotective effect of transient ischemic stress in the isolated rat heart is mediated by
1-adrenergic
receptors.7 Although other factors are no doubt also
involved,29 modest ischemic episodes are apparently sensed
by adrenergic nerve termini, resulting in exocytotic norepinephrine
release into the neuromuscular synapse.7 30 Logically,
stimulation of 1-adrenergic receptors should confer the
cardioprotective state through the signaling system associated with
these receptors. Our results demonstrate that both transient ischemia
and 1-adrenergic receptor agonist–induced functional
preconditioning are inhibited by PKC blockade. Also, both transient
ischemia and 1-adrenergic receptor stimulation induce
PKC translocation. Moreover, administration of the endogenous PKC
activator DAG produces similar cardioprotection against IR. Therefore,
PKC appears to be an integral second messenger involved in transient
ischemic or receptor-stimulated preconditioning of the isolated rat
heart.
1-Adrenergic receptor–stimulated activation of PKC has
been demonstrated in a variety of cardiac cell types, including the
myocyte. In addition to prominent hemodynamic effects, these receptors
are implicated in multiple effects, including hypertrophic and
metabolic remodeling.13 14 15 31 Transduction of the
1-adrenergic receptor signal13 14 15 31 occurs
via a G protein that stimulates a phosphatidylinositol-specific
phospholipase C producing IP3 and DAG species. DAG binding
to the conventional Ca2+-dependent cPKCs lowers the
Km for Ca2+ into the physiological
range. The recently discovered novel nPKCs are directly activated
without the need for Ca2+. Unlike DAG, which is rapidly
degraded, 4ß-phorbol esters are not metabolized and are associated
with sustained PKC activation and pathological changes. Occupation of
the regulatory site induces intracellular PKC translocation. This
partition mechanism is characterized by increased affinity for acidic
lipids and increased activation in their presence. Regulator-induced
translocation and activation of PKC may be inseparable events, since
occupation of the regulatory domain removes an N-terminal inhibitory
(pseudosubstrate) sequence from its close juxtaposition to the
catalytic site (C5).15 Thus, translocation from cytosolic
to organellar compartments is useful as a marker for activated PKC (Fig 5
).
Protein kinases control different aspects of cellular homeostasis,
including metabolic pathways, cytoskeletal function, secretion, and
growth via phosphorylation of target proteins. In myocardium,
1-adrenergic receptor stimulation promotes
32P labeling of myofibrillar, membranous, nuclear, and
cytosolic proteins. The physiological implications of changes in
affinity and activity in target proteins after
phosphorylation,14 32 33 especially in the context of
protection against IR injury, are unclear.
Isoform-Specific Activation of PKC
Many studies of cardiac 1-adrenergic receptor
transduction and physiology preceded the implicit recognition of the
different PKC isoforms, each with specific localization and substrate
selectivity profiles. This problem is further confounded by the use of
4ß-phorbol esters to probe the physiological role of PKC in the
heart. These long-acting tumor promoters do not mimic the functional
consequences of 1-adrenergic receptor
stimulation.34 35 36 Nevertheless, certain features such as
intracellular alkalinization via Na+-H+
exchange and increased myofibrillar Ca2+ sensitivity appear
common to both 1-adrenergic receptor stimulation and
direct 4ß-phorbol ester stimulation.
We compared the distinct isoforms of PKC stimulated by transient
ischemia or phenylephrine (Fig 5). Our immunohistofluorescence studies
demonstrate translocation of the PKC- isoform early in the window of
protection following both preconditioning stimuli. In addition,
transient ischemia results in PKC- translocation into the nucleus.
This difference may arise from additional signals that are part of
transient ischemia (eg, adenosine and ß-adrenergic signals).
Interestingly, PKC translocation into the nucleus may regulate gene
transcription.15 37 38 Given the short interval between
transient ischemia and sustained ischemia as well as the reported
immunity to cycloheximide/actinomycin blockade,39 nuclear
transcription events are not likely involved in mediating the early
window of protection associated with preconditioning. However, the
translocation of PKC- across the nuclear membrane may be related to
a delayed window of protection induced by
preconditioning.3 40 41
In isolated adult rat myocytes disrupted by freeze-thawing or
detergent, fractionated, and then subjected to sodium dodecyl
sulfate–polyacrylamide gel electrophoresis followed by Western
blotting, only PKC- could be detected.19 This lone
detected isoform was found to translocate to membrane fractions when
stimulated by phorbol ester and less so after epinephrine and
endothelin.19 The primary antibodies used to probe for
PKC- (664 to 673) and PKC- (721 to 737) were raised against
similar isotype-specific sequences in the V5 C-terminal region of PKC
as used in the present study. In the present study, we have
localized the translocation of PKC- into the perinuclear membranes
after transient ischemic or phenylephrine stimulation (Fig 5).
Direct immunofluorescence on heart cryosections disrupts the cellular
architecture to a minimal degree. However, antibody-based techniques
for isoform detection suffer from the potential for cross-reactivity.
Therefore, we have included for consideration only those PKC isoforms
(PKC-, -, and -) that consistently translocated between
intracellular compartments. The significance of the PKC- isoform in
preconditioning is accented by its common translocation to the
sarcolemma (Fig 5) after stimulation by either transient ischemia or
its mechanistic intermediary, the 1-adrenergic receptor
(PE, Fig 1). Other investigators have performed immunohistofluorescence
studies by using PKC antibodies from the same commercial source used in
the present study.28 In contrast with our results in
perfused adult hearts, these investigators found that PKC- and
PKC- isoforms in cultured neonatal rat myocytes are predominantly
intranuclear. These isoforms migrated to the perinuclear membrane after
either phorbol 12-myristate 13-acetate (PMA) or norepinephrine
exposure. Neither PMA nor norepinephrine translocated any isoform to
the sarcolemma in cultured neonatal myocytes. Moreover, the presence of
serum in the cultures resulted in markedly different morphology. Thus,
the PKC isoform distribution and translocation described in the
present study may be characteristic of the adult intact heart
preparation and the receptor stimuli.
PKC activation in the heart is apparently not restricted to receptor
control. PKC activity apparently translocates to membrane compartments
during sustained ischemia23 42 and could be detected as
Ca2+-dependent phosphorylation of histone
III-S.23 These are characteristics of cPKC isoforms; thus,
the PKC activity translocation in homogenized and fractionated ischemic
tissue may be distinct from the nPKC isoforms that appear to be
mobilized by receptor stimuli19 (Fig 5).
Potential Mechanism of Preconditioning by PKC
The signal transduction cascades of a large number of receptors
are coupled to PKC activation.20 43 44 45 Consequently, other
receptors that involve PKC (showing disparate hemodynamics) could
theoretically lead to preconditioning. The differing physiological
effects of various receptors sharing PKC in their transduction cascades
may involve an interplay of receptor-specific activation of selected
isoforms and the unique/distinctive translocation of a particular
isoform(s) to specific compartments within the cell28 (Fig 5).
A causal relation between immediate hemodynamics and functional
preconditioning is also refuted by the disparate hemodynamics of
transient ischemia (severe contractile depression), phenylephrine
(stimulation), and DAG (minor depression). The PKC blockers
staurosporine and chelerythrine (Figs 2 and 3) abolished protection and
selectively attenuated the third phase of sustained inotropy after
phenylephrine stimulation. However, this association is negated by the
endogenous activator of PKC, DAG, which only stimulates a modest
negative inotropic phase (Fig 4). This suggests that preconditioning
may be mediated by PKC isoforms selected by transient ischemia and
phenylephrine that do not bear directly on hemodynamics.
Since PKC translocation to membranous compartments has been associated
with sustained ischemia,23 PKC might contribute to
ischemic injury. Membrane-associated PKC is known to be susceptible to
proteolytic cleavage and degradation.15 Therefore,
detrimental PKC activity during ischemia could be downregulated because
of initial activation and translocation by transient ischemia or
phenylephrine. However, our findings do not substantiate this
mechanism. PKC blockade with either staurosporine or chelerythrine did
not protect cardiac function (Figs 2 and 3). Similarly, others have
reported that PKC blockade with staurosporine or polymyxin B also did
not protect against ischemia in rabbit hearts.20
PKC regulates intracellular processes not only by direct
phosphorylation of numerous rate-limiting enzyme targets but also by
initiating other protein kinase cascades. Potentially protective
effects of 1-adrenergic receptor stimulation that might
contribute to preconditioning could include desensitization of
deleterious pathways (eg, ß-adrenergic receptors9 46 ) or
preemptive cellular alkalinization14 47 before ischemia.
In addition, proactive measures such as myofilament
sensitization,14 48 5'-nt–mediated adenosine
formation,9 and upregulated reenergization could also be
important.7 49 50 An added dimension of control is exerted
by signal cross talk, wherein PKC phosphorylation modulates other
pathways (eg, cAMP-dependent protein kinase and calmodulin-dependent
kinase).14 51 Therefore, a necessary consequence of PKC
activation is the eventual modulation of its own as well as parallel
transduction pathways.
Signal Convergence at PKC
Mechanistic studies of preconditioning in rats7 and
rabbits8 20 are converging on the potentially unifying
role of PKC. There are significant differences between these studies.
In rats, we have discovered that 1-adrenergic
stimulation and PKC activation are both necessary and sufficient
conditions for inducing functional preconditioning (SAG, Fig 4;
blockade, Figs 2 and 3). In contrast, the anti-infarction
preconditioning in rabbit is predominantly adenosine
A1/A3 receptor–mediated.10
Moreover, rabbit anti-infarction preconditioning is inducible by
broad-spectrum PKC isoform activation using phorbol
esters.8 20
On the basis of the attenuation of phorbol-induced cardioprotection by the adenosine P1 receptor antagonist, Cohen and Downey8 and Ytrehus et al20 have recently proposed an intriguing two-step hypothesis. In this proposal, primary PKC translocation stimulated by receptors or ischemia is not followed by activation/phosphorylation. Reoccupation of adenosine A1 receptors during sustained ischemia is necessary before previously translocated PKC can phosphorylate proteins.20 These authors suggest that the blockade of protection observed by PKC inhibitors given 5 minutes after preconditioning ischemia implies that phosphorylation by translocated PKC occurs under conditions of sustained ischemia.8 20
This hypothesis challenges the concept of PKC conformational changes induced by regulatory site occupation leading to concomitant translocation and activation.15 Additionally, this hypothesis suggests that adenosine P1 receptor stimulation modifies PKC activity in heart tissue. It is unknown whether adenosine A1 receptors stimulate PKC translocation in rabbit and, if so, how slowly. The proposed requirement that PKC translocated by DAG be stable20 until ischemic adenosine is available is difficult to reconcile with the notion that receptor-stimulated PKC translocation may be quite labile.27
PKC translocation after ischemic periods has been detected by activity
assays23 42 and been found to be
1-adrenergic receptor independent. If preconditioning
adenosine receptors act through DAG and if PKC executes preconditioning
during ischemia, then adenosine formed during ischemia should be
adequate to activate PKC and provide automatic protection in untreated
hearts. Nevertheless, adenosine receptor blockade does not appear to
increase IR injury.20 29 Indeed, lowered free energy of
ATP hydrolysis (and/or high ADP and inorganic phosphate concentrations)
during prolonged ischemia is likely to alter the selectivity and extent
of protein phosphorylation by PKC isoforms compared with normally
perfused conditions.
Our results show that PKC translocation in rat after either transient ischemia or phenylephrine is rapid, being evident after 2 minutes of phenylephrine, and is nPKC isoform selective. The early activation of the kinase is consistent with the concept that protection develops during the preconditioning window,7 52 before the onset of sustained ischemia. Among a variety of blockade protocols investigated in the present study, preconditioning effects were blocked best when the antagonists were present in the immediate temporal vicinity of the preconditioning stimuli. The gradual appearance of protection during the preconditioning window7 52 is consistent with the intrinsic energy dependence of PKC phosphorylation (ie, its ATPase action). Furthermore, the gradual decay of protection during the same conditioning window53 54 55 56 is also consistent with reversible translocation and dephosphorylation steps within preconditioning.57 Therefore, the cardioprotective response of preconditioning may be determined both by the receptor-selected isoform(s) and by the energetics and time windows separating PKC stimulation from sustained ischemia.
It also remains to be determined whether PKC activation8
by exogenous adenosine (or selective A1 agonist),
muscarinic M2, and 1-adrenergic receptor
agonists shares common PKC isoforms. Nevertheless, the findings of
DAG-induced cardioprotection and elimination of preconditioning by PKC
inhibitors suggest that PKC is a mediator common to both the rat and
rabbit.
Conclusions
In the present study, we have observed early activation of
selected PKC isoforms (Fig 5) after preconditioning stimuli. These
findings are corroborated by functional studies in which PKC activation
promotes preconditioning and PKC blockade eliminates this effect. The
targets of subsequent phosphorylation reactions remain unexplored.
Therefore, the present set of experiments do not go further than to
implicate PKC in the preconditioning mechanism. Since PKC inhibition
blocks preconditioning but has no protective effect on the control
condition, the mechanism of this cardioadaptation toward IR appears to
involve positive protective actions of PKC.
|
Acknowledgments |
|---|
This study was supported in part by National Institutes of Health grants R01 HL-44186-03 (Dr Harken), R29 HL-43696 (Dr Banerjee), and T32-GMO8315-01. The technical assistance and expert comments of Daniel Chan are gratefully acknowledged.
|
Footnotes |
|---|
Reprint requests to Anirban Banerjee, 4200 E Ninth Ave, Box C-310, Denver, CO 80262.
Received March 17, 1994; accepted September 14, 1994.
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References |
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S. A. Gabel, R. E. London, C. D. Funk, C. Steenbergen, and E. Murphy Leukocyte-type 12-lipoxygenase-deficient mice show impaired ischemic preconditioning-induced cardioprotection Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1963 - H1969. [Abstract] [Full Text] [PDF]
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J. M. Pass, Y. Zheng, W. B. Wead, J. Zhang, R. C. X. Li, R. Bolli, and P. Ping PKC{epsilon} activation induces dichotomous cardiac phenotypes and modulates PKC{epsilon}-RACK interactions and RACK expression Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H946 - H955. [Abstract] [Full Text] [PDF]
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R. M. Fryer, Y. Wang, A. K. Hsu, and G. J. Gross Essential activation of PKC-{delta} in opioid-initiated cardioprotection Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1346 - H1353. [Abstract] [Full Text] [PDF]
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S. Shigematsu, S. Ishida, D. C. Gute, and R. J. Korthuis Postischemic anti-inflammatory effects of bradykinin preconditioning Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H441 - H454. [Abstract] [Full Text] [PDF]
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S. Pepe Dysfunctional ischemic preconditioning mechanisms in aging Cardiovasc Res, January 1, 2001; 49(1): 11 - 14. [Full Text] [PDF]
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M. Tani, Y. Honma, H. Hasegawa, and K. Tamaki Direct activation of mitochondrial KATP channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts Cardiovasc Res, January 1, 2001; 49(1): 56 - 68. [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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R. C. X. Li, P. Ping, J. Zhang, W. B. Wead, X. Cao, J. Gao, Y. Zheng, S. Huang, J. Han, and R. Bolli PKCepsilon modulates NF-kappa B and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1679 - H1689. [Abstract] [Full Text] [PDF]
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W. G. Pyle, T. D. Smith, and P. A. Hofmann Cardioprotection with kappa -opioid receptor stimulation is associated with a slowing of cross-bridge cycling Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1941 - H1948. [Abstract] [Full Text] [PDF]
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T. Pain, X.-M. Yang, S. D. Critz, Y. Yue, A. Nakano, G. S. Liu, G. Heusch, M. V. Cohen, and J. M. Downey Opening of Mitochondrial KATP Channels Triggers the Preconditioned State by Generating Free Radicals Circ. Res., September 15, 2000; 87(6): 460 - 466. [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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H. Tong, W. Chen, C. Steenbergen, and E. Murphy Ischemic Preconditioning Activates Phosphatidylinositol-3-Kinase Upstream of Protein Kinase C Circ. Res., August 18, 2000; 87(4): 309 - 315. [Abstract] [Full Text] [PDF]
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R. A. Hopper, C. R. Forrest, H. Xu, A. Zhong, W. He, J. Rutka, P. Neligan, and C. Y. Pang Role and mechanism of PKC in ischemic preconditioning of pig skeletal muscle against infarction Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R666 - R676. [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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K.-I. Kawabata, T. Netticadan, M. Osada, K. Tamura, and N. S. Dhalla Mechanisms of ischemic preconditioning effects on Ca2+ paradox-induced changes in heart Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H1008 - H1015. [Abstract] [Full Text] [PDF]
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K. Inagaki, Y. Kihara, W. Hayashida, T. Izumi, Y. Iwanaga, T. Yoneda, Y. Takeuchi, K. Suyama, E. Muso, and S. Sasayama Anti-Ischemic Effect of a Novel Cardioprotective Agent, JTV519, Is Mediated Through Specific Activation of {delta}-Isoform of Protein Kinase C in Rat Ventricular Myocardium Circulation, February 22, 2000; 101(7): 797 - 804. [Abstract] [Full Text] [PDF]
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J.-F. Bouchard, J. Chouinard, and D. Lamontagne Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart Cardiovasc Res, January 14, 2000; 45(2): 418 - 427. [Abstract] [Full Text] [PDF]
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E. Takashi, Y. Wang, and M. Ashraf Activation of Mitochondrial KATP Channel Elicits Late Preconditioning Against Myocardial Infarction via Protein Kinase C Signaling Pathway Circ. Res., December 3, 1999; 85(12): 1146 - 1153. [Abstract] [Full Text] [PDF]
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A. Gysembergh, S. Lemaire, C. Piot, C. Sportouch, S. Richard, R. A. Kloner, and K. Przyklenk Pharmacological manipulation of Ins(1,4,5)P3 signaling mimics preconditioning in rabbit heart Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2458 - H2469. [Abstract] [Full Text] [PDF]
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J. M. Davis, D. C. Gute, S. Jones, A. Krsmanovic, and R. J. Korthuis Ischemic preconditioning prevents postischemic P-selectin expression in the rat small intestine Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2476 - H2481. [Abstract] [Full Text] [PDF]
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K. L. Butler, A. H. Huang, and J. K. Gwathmey AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2482 - H2487. [Abstract] [Full Text] [PDF]
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 R. Tian, W. Miao, M. Spindler, M. M. Javadpour, R. McKinney, J. C. Bowman, P. M. Buttrick, and J. S. Ingwall Long-term expression of protein kinase C in adult mouse hearts improves postischemic recovery PNAS, November 9, 1999; 96(23): 13536 - 13541. [Abstract] [Full Text] [PDF]
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F. G. Spinale Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest Ann. Thorac. Surg., November 1, 1999; 68(5): 1934 - 1941. [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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C.-H. Chen, M. O. Gray, and D. Mochly-Rosen Cardioprotection from ischemia by a brief exposure to physiological levels of ethanol: Role of epsilon protein kinase C PNAS, October 26, 1999; 96(22): 12784 - 12789. [Abstract] [Full Text] [PDF]
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G. W. Dorn II, M. C. Souroujon, T. Liron, C.-H. Chen, M. O. Gray, H. Z. Zhou, M. Csukai, G. Wu, J. N. Lorenz, and D. Mochly-Rosen Sustained in vivo cardiac protection by a rationally designed peptide that causes varepsilon protein kinase C translocation PNAS, October 26, 1999; 96(22): 12798 - 12803. [Abstract] [Full Text] [PDF]
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X.-H. Xiao and D. G. Allen Role of Na+/H+ Exchanger During Ischemia and Preconditioning in the Isolated Rat Heart Circ. Res., October 15, 1999; 85(8): 723 - 730. [Abstract] [Full Text] [PDF]
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Y. Wang, K. Hirai, and M. Ashraf Activation of Mitochondrial ATP-Sensitive K+ Channel for Cardiac Protection Against Ischemic Injury Is Dependent on Protein Kinase C Activity Circ. Res., October 15, 1999; 85(8): 731 - 741. [Abstract] [Full Text] [PDF]
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L. R.C. Dekker, R. Coronel, E. VanBavel, J. A.E. Spaan, and T. Opthof Intracellular Ca2+ and delay of ischemia-induced electrical uncoupling in preconditioned rabbit ventricular myocardium Cardiovasc Res, October 1, 1999; 44(1): 101 - 112. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, Y.-T. Zheng, R. C. X. Li, B. Dawn, X.-L. Tang, H. Takano, Z. Balafanova, and R. Bolli Demonstration of Selective Protein Kinase C–Dependent Activation of Src and Lck Tyrosine Kinases During Ischemic Preconditioning in Conscious Rabbits Circ. Res., September 17, 1999; 85(6): 542 - 550. [Abstract] [Full Text] [PDF]
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A. Rizvi, X.-L. Tang, Y. Qiu, Y.-T. Xuan, H. Takano, A. K. Jadoon, and R. Bolli Increased protein synthesis is necessary for the development of late preconditioning against myocardial stunning Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H874 - H884. [Abstract] [Full Text] [PDF]
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J. L. Lundmark, R. Ramasamy, P. R. Vulliet, and S. Schaefer Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H999 - H1006. [Abstract] [Full Text] [PDF]
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Y. Takeishi, T. Jalili, N. A. Ball, and R. A. Walsh Responses of Cardiac Protein Kinase C Isoforms to Distinct Pathological Stimuli Are Differentially Regulated Circ. Res., August 6, 1999; 85(3): 264 - 271. [Abstract] [Full Text] [PDF]
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Y. V. Ladilov, C. Balser-Schafer, S. Haffner, H. Maxeiner, and H.M. Piper Pretreatment with PKC activator protects cardiomyocytes against reoxygenation-induced hypercontracture independently of Ca2+ overload Cardiovasc Res, August 1, 1999; 43(2): 408 - 416. [Abstract] [Full Text] [PDF]
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R. H. Strasser, G. Simonis, S. P. Schon, M. U. Braun, R. Ihl-Vahl, C. Weinbrenner, R. Marquetant, and W. Kubler Two Distinct Mechanisms Mediate a Differential Regulation of Protein Kinase C Isozymes in Acute and Prolonged Myocardial Ischemia Circ. Res., July 9, 1999; 85(1): 77 - 87. [Abstract] [Full Text] [PDF]
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D. J. Hearse and F. J. Sutherland Catecholamines and preconditioning: studies of contraction and function in isolated rat hearts Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H136 - H143. [Abstract] [Full Text] [PDF]
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S. Takeo and Y. Nasa Role of energy metabolism in the preconditioned heart - a possible contribution of mitochondria Cardiovasc Res, July 1, 1999; 43(1): 32 - 43. [Abstract] [Full Text] [PDF]
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S. Egert, N. Nguyen, and M. Schwaiger Contribution of {alpha}-Adrenergic and ß-Adrenergic Stimulation to Ischemia-Induced Glucose Transporter (GLUT) 4 and GLUT1 Translocation in the Isolated Perfused Rat Heart Circ. Res., June 25, 1999; 84(12): 1407 - 1415. [Abstract] [Full Text] [PDF]
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W. Chen, W. Glasgow, E. Murphy, and C. Steenbergen Lipoxygenase metabolism of arachidonic acid in ischemic preconditioning and PKC-induced protection in heart Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2094 - H2101. [Abstract] [Full Text] [PDF]
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Y. Wang and M. Ashraf Role of Protein Kinase C in Mitochondrial KATP Channel–Mediated Protection Against Ca2+ Overload Injury in Rat Myocardium Circ. Res., May 28, 1999; 84(10): 1156 - 1165. [Abstract] [Full Text] [PDF]
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X. Meng, B. D. Shames, E. J. Pulido, D. R. Meldrum, L. Ao, K. S. Joo, A. H. Harken, and A. Banerjee Adrenergic induction of bimodal myocardial protection: signal transduction and cardiac gene reprogramming Am J Physiol Regulatory Integrative Comp Physiol, May 1, 1999; 276(5): R1525 - R1533. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, X. Cao, R. C. X. Li, D. Kong, X.-L. Tang, Y. Qiu, S. Manchikalapudi, J. A. Auchampach, R. G. Black, et al. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1468 - H1481. [Abstract] [Full Text] [PDF]
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N. L. Bernardo, M. D'Angelo, S. Okubo, A. Joy, and R. C. Kukreja Delayed ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1323 - H1330. [Abstract] [Full Text] [PDF]
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P. Ping, H. Takano, J. Zhang, X.-L. Tang, Y. Qiu, R. C. X. Li, S. Banerjee, B. Dawn, Z. Balafonova, and R. Bolli Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits : A Signaling Mechanism for Both Nitric Oxide–Induced and Ischemia-Induced Preconditioning Circ. Res., March 19, 1999; 84(5): 587 - 604. [Abstract] [Full Text] [PDF]
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K. Hu, G.-R. Li, and S. Nattel Adenosine-induced activation of ATP-sensitive K+ channels in excised membrane patches is mediated by PKC Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H488 - H495. [Abstract] [Full Text] [PDF]
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C. J. Albert and D. A. Ford Protein kinase C translocation and PKC-dependent protein phosphorylation during myocardial ischemia Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H642 - H650. [Abstract] [Full Text] [PDF]
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S. Kawamura, K.-I. Yoshida, T. Miura, Y. Mizukami, and M. Matsuzaki Ischemic preconditioning translocates PKC-delta and -epsilon , which mediate functional protection in isolated rat heart Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2266 - H2271. [Abstract] [Full Text] [PDF]
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N. Maulik, T. Yoshida, Y.-L. Zu, M. Sato, A. Banerjee, and D. K. Das Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2 Am J Physiol Heart Circ Physiol, November 1, 1998; 275(5): H1857 - H1864. [Abstract] [Full Text] [PDF]
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S. Perlini, E. P. Khoury, G. R. Norton, E. S. Chung, R. A. Fenton, J. G. Dobson Jr, and T. E. Meyer Adenosine Mediates Sustained Adrenergic Desensitization in the Rat Heart via Activation of Protein Kinase C Circ. Res., October 5, 1998; 83(7): 761 - 771. [Abstract] [Full Text] [PDF]
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B. Z. Simkhovich, K. Przyklenk, and R. A. Kloner Role of protein kinase C as a cellular mediator of ischemic preconditioning: a critical review Cardiovasc Res, October 1, 1998; 40(1): 9 - 22. [Abstract] [Full Text] [PDF]
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J. Zhao, O. Renner, L. Wightman, P. H. Sugden, L. Stewart, A. D. Miller, D. S. Latchman, and M. S. Marber The Expression of Constitutively Active Isotypes of Protein Kinase C to Investigate Preconditioning J. Biol. Chem., September 4, 1998; 273(36): 23072 - 23079. [Abstract] [Full Text] [PDF]
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T. F. Rehring, J. I. Shapiro, B. S. Cain, D. R. Meldrum, J. C. Cleveland, A. H. Harken, and A. Banerjee Mechanisms of pH preservation during global ischemia in preconditioned rat heart: roles for PKC and NHE Am J Physiol Heart Circ Physiol, September 1, 1998; 275(3): H805 - H813. [Abstract] [Full Text] [PDF]
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 A. Clerk, A. Michael, and P. H. Sugden Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein-coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy? J. Cell Biol., July 27, 1998; 142(2): 523 - 535. [Abstract] [Full Text] [PDF]
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T. J. Rohs, K. S. Kilgore, A. J. Georges, and S. F. Bolling Postischemic Function and Protein Kinase C Signal Transduction Ann. Thorac. Surg., June 1, 1998; 65(6): 1680 - 1684. [Abstract] [Full Text] [PDF]
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R. A. Kloner, R. Bolli, E. Marban, L. Reinlib, and E. Braunwald Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning : An NHLBI Workshop Circulation, May 19, 1998; 97(18): 1848 - 1867. [Full Text] [PDF]
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L. R. C. Dekker, H. Rademaker, J. T. Vermeulen, T. Opthof, R. Coronel, J. A. E. Spaan, and M. J. Janse Cellular Uncoupling During Ischemia in Hypertrophied and Failing Rabbit Ventricular Myocardium : Effects of Preconditioning Circulation, May 5, 1998; 97(17): 1724 - 1730. [Abstract] [Full Text] [PDF]
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I. Kouchi, T. Murakami, R. Nawada, M. Akao, and S. Sasayama KATP channels are common mediators of ischemic and calcium preconditioning in rabbits Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1106 - H1112. [Abstract] [Full Text] [PDF]
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D. R. Meldrum Tumor necrosis factor in the heart Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1998; 274(3): R577 - R595. [Abstract] [Full Text] [PDF]
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H. Miyawaki, Y. Wang, and M. Ashraf Oxidant stress with hydrogen peroxide attenuates calcium paradox injury: role of protein kinase C and ATP-sensitive potassium channel Cardiovasc Res, March 1, 1998; 37(3): 691 - 699. [Abstract] [Full Text] [PDF]
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L. R.C Dekker Toward the heart of ischemic preconditioning Cardiovasc Res, January 1, 1998; 37(1): 14 - 20. [Full Text] [PDF]
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J.-F. Bouchard and D. Lamontagne Protection afforded by preconditioning to the diabetic heart against ischaemic injury Cardiovasc Res, January 1, 1998; 37(1): 82 - 90. [Abstract] [Full Text] [PDF]
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M. O. Gray, J. S. Karliner, and D. Mochly-Rosen A Selective epsilon -Protein Kinase C Antagonist Inhibits Protection of Cardiac Myocytes from Hypoxia-induced Cell Death J. Biol. Chem., December 5, 1997; 272(49): 30945 - 30951. [Abstract] [Full Text] [PDF]
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S.-J. O, M. H. Cox, F. A. Crawford Jr., and F. G. Spinale PROTEIN KINASE C ACTIVATION BEFORE CARDIOPLEGIC ARREST: BENEFICIAL EFFECTS ON MYOCYTE CONTRACTILITY J. Thorac. Cardiovasc. Surg., October 1, 1997; 114(4): 651 - 659. [Abstract] [Full Text]
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T. Oxman, M. Arad, R. Klein, N. Avazov, and B. Rabinowitz Limb ischemia preconditions the heart against reperfusion tachyarrhythmia Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1707 - H1712. [Abstract] [Full Text] [PDF]
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