1 Department of Cardiology, Royal North Shore Hospital, and 2 University of Sydney, Sydney, New South Wales, Australia 2065
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ABSTRACT |
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A reduction in angiotensin
II (ANG II) in vivo by treatment of rabbits with the
angiotensin-converting enzyme inhibitor, captopril, increases
Na+-K+ pump current (Ip)
of cardiac myocytes. This increase is abolished by exposure of myocytes
to ANG II in vitro. Because ANG II induces translocation of the
-isoform of protein kinase C (PKC
), we examined whether this
isozyme regulates the pump. We treated rabbits with captopril, isolated
myocytes, and measured Ip of myocytes voltage
clamped with wide-tipped patch pipettes. Ip of
myocytes from captopril-treated rabbits was larger than
Ip of myocytes from controls. ANG II superfusion
of myocytes from captopril-treated rabbits decreased
Ip to levels similar to controls. Inclusion of
PKC
-specific blocking peptide in pipette solutions used to perfuse
the intracellular compartment abolished the effect of ANG II. Inclusion
of
RACK, a PKC
-specific activating peptide, in pipette
solutions had an effect on Ip that was similar
to that of ANG II. There was no additive effect of ANG II and
RACK. We conclude that PKC
regulates the sarcolemmal
Na+-K+ pump.
intracellular sodium; protein kinase C isozymes; cardiac myocytes; angiotensin; cardiac hypertrophy
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INTRODUCTION |
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IT IS WIDELY BELIEVED that the protein kinase C (PKC) family of isozymes is involved in the control of the membrane Na+-K+ pump (see Ref. 30 for review). Multiple, very diverse isozymes of PKC are known to exist. They differ in their cellular location, site of translocation upon activation, sensitivity to cell Ca2+, lipid activators, pharmacological blockers and activators, and in their functional role within the cell. Evidence is also emerging that indicates that isozymes of PKC differ in their involvement in disease processes, and it has been suggested that isozyme-specific stimulation or inhibition of PKC may have a role in the treatment of a variety of diseases (3, 5).
Establishing a link between isozymes of PKC and regulation of the sarcolemmal Na+-K+ pump is important because the pump plays a pivotal role in cell function. The pump is the main determinant of low cytosolic levels of Na+. It is widely appreciated that this, in turn, drives secondary active transmembrane transport of other ions and of a variety of organic compounds. Cell volume, metabolism, excitation, and excitation-contraction coupling depend on these processes (30). However, it has also become apparent that the Na+-K+ pump has an even more broadly based role in cell function, at least in the heart. Pump inhibition induces activation of key growth-related cardiac genes and generation of reactive oxygen species (see Refs. 14 and 31 and references therein). The Na+-K+ pump may, therefore, represent an important link between specific isozymes of PKC and cardiac function and disease. We examined whether PKC isoform-specific regulation of the sarcolemmal Na+-K+ pump can be identified.
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MATERIALS AND METHODS |
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Treatment protocols and experimental design. Male New Zealand White rabbits that weighed 2.5-3.0 kg were given the angiotensin-converting enzyme (ACE) inhibitor captopril in their drinking water for 8 days (11) to reduce background levels of angiotensin II (ANG II). Control rabbits were given captopril-free water. At the completion of treatment, rabbits were anesthetized with an intramuscular injection of ketamine (50 mg/kg) and xylazine hydrochloride (20 mg/kg), the heart was excised, and single ventricular myocytes were isolated as described previously (11). Treatment with captopril caused an increase in electrogenic Na+-K+ current (Ip) measured in the isolated myocytes. The increase was abolished by in vitro exposure to ANG II (1, 10). To examine whether a specific isoform of PKC can be implicated in the regulation of the sarcolemmal Na+-K+ pump, we used this effect of ANG II to induce a decrease in Ip of myocytes isolated from rabbits treated with captopril.
Measurement of Ip.
We used the whole cell patch-clamp technique to measure
Ip. Myocytes were initially superfused with
modified Tyrode solution warmed to 35 ± 0.5°C. The solution
contained (in mM) 140 NaCl, 5.6 KCl, 2.16 CaCl2, 1 MgCl2, 0.44 NaH2PO4, 10 glucose,
and 10 HEPES, pH 7.40 ± 0.01 at 35°C. When the whole cell
configuration had been established, we switched to a superfusate that
was identical, except it was nominally Ca2+ free and
contained 0.2 mM CdCl2 to reduce
Na+/Ca2+ exchange current and 2 mM
BaCl2 to block K+ channel currents.
When indicated, this solution contained ANG II in a
concentration of 1 µM. Ip was measured at a
membrane voltage of 40 mV to block voltage-sensitive Na+
channels. The inhibition of non-pump membrane currents facilitates accurate identification of Ip.
Reagents and chemicals. TMA-Cl was "purum" grade and purchased from Fluka (Switzerland). Other chemicals were analytical grade and purchased from BDH (Australia). ANG II and ouabain were purchased from Sigma Chemical (St. Louis, MO). Captopril was purchased from Bristol-Myers Squibb Pharmaceuticals (Australia). PKC-inhibiting and -activating peptides were kindly provided by Professor D. Mochly-Rosen (Stanford University School of Medicine, Stanford, CA).
Statistical analysis. Results are expressed as means ± SE. One-way ANOVA was used for statistical comparisons. Where the same control group was used in more than one comparison, Dunnett's test was used to compare groups. P < 0.05 is regarded as significant in all comparisons.
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RESULTS |
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Effect of ANG II on Ip. In previous studies, an increase in Ip induced by in vivo treatment of rabbits with the ACE inhibitor captopril could be abolished by in vitro exposure of myocytes to 10 nM ANG II for 45 min before the whole cell configuration was established (1, 10). In the present study, PKC-inhibiting and -activating peptides had to diffuse from patch pipette solutions into the intracellular compartment before myocytes were exposed to ANG II. Maintaining the whole cell configuration for 45 min is difficult. In initial experiments, we therefore examined whether a decrease in Ip could be induced with brief exposure of myocytes to ANG II after the whole cell configuration had been established.
To facilitate rapid binding to receptors and activation of intracellular messengers before measurement of Ip, we used ANG II in a concentration of 1 µmol/l rather than the 10 nM used previously. We isolated myocytes from rabbits treated with captopril. When the whole cell configuration had been established, we measured membrane capacitance while the myocytes were superfused with Ca2+-containing solution. This solution was ANG II free. We then switched to a superfusate that was Ca2+ free and contained Ba2+, Cd2+, and ANG II. The myocytes were exposed to this solution for 10 min before Ip was identified as the shift in holding current, induced by switching to a solution that also included 100 µM ouabain. Superfusion of ouabain in these and all other experiments was started 14 min after the whole cell configuration had been established. Tracings of representative changes in membrane currents induced by ouabain recorded in myocytes exposed or not exposed to ANG II are shown in Fig. 1. The ouabain-induced shift in current was smaller for a myocyte exposed to ANG II than a myocyte superfused with ANG II-free solution throughout the experiment. A summary of mean levels of Ip determined in all such experiments is shown in Fig. 2. Figure 2 also shows the mean levels of Ip determined for myocytes isolated from untreated control rabbits. In agreement with previous findings (1, 10), treatment with captopril induced a significant increase in Ip. Exposure of myocytes isolated from captopril-treated rabbits to ANG II induced a decrease in Ip to a level similar to that recorded in myocytes isolated from untreated control rabbits and not exposed to ANG II in vitro. The level was also similar to the mean Ip of myocytes isolated from rabbits treated with captopril and exposed to 10 nM ANG II for 45 min before the whole cell configuration was established (1, 10). We conclude that the cellular messenger mechanisms linking the ANG II receptor to the Na+-K+ pump remain intact after the whole cell configuration has been established and that brief exposure of patch-clamped myocytes to ANG II causes an easily detectable decrease in Ip. We used this response of Ip to examine whether an isoform of PKC can be implicated in the regulation of the Na+-K+ pump.
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Effect of PKC inhibition on the response of Ip to ANG
II.
ANG II predominantly induces translocation of the classical PKC
isozymes and the novel -isozyme. Of these, the
Ca2+-insensitive PKC
is more likely to be involved in a
response elicited in myocytes exposed to a nominally
Ca2+-free superfusate at the extracellular surface and to
an EGTA-containing patch pipette solution perfusing the intracellular
compartment. We examined the effect of blockade of PKC
. We patch
clamped myocytes isolated from captopril-treated rabbits using pipettes
with a filling solution that included a PKC
-blocking peptide
(EAVSLKPT). After the whole cell configuration was achieved, myocytes
were exposed to ANG II before Ip was determined,
as described for experiments performed without a PKC
-blocking
peptide in pipette solutions. Figure 1 includes a representative trace
of membrane currents. Ip was similar to the
Ip for the myocyte not exposed to ANG II (Fig.
1, top). The mean level of Ip of all
experiments performed using both ANG II-containing superfusates and a
PKC
-blocking peptide in pipette solutions is shown in Fig. 2. The
peptide abolished the effect of ANG II on Ip.
Effect of PKC activation on Ip.
To examine whether the effect of ANG II on Ip
could be reproduced by directly activating PKC
, we patch clamped
myocytes from captopril-treated rabbits using pipette solutions that
contained 100 nM of the agonist
RACK (HDAPIGYD) (7).
The myocytes were not exposed to ANG II before
Ip was determined. The mean level of
Ip, included in Fig. 2, was similar to levels
for myocytes exposed to ANG II and myocytes that were patch clamped
using pipette solutions free of activating peptide. To examine
whether the decrease in Ip was caused by a
nonspecific effect of the charge of
RACK, we performed
experiments using 100 nM of a scrambled form of the peptide (PDYHDAGI)
in pipette filling solutions. It had no effect on
Ip (Fig. 2). We next examined whether there was
an additive effect of ANG II and
RACK. We patch clamped myocytes
from captopril-treated rabbits using pipette solutions that contained
RACK. The myocytes were exposed to ANG II before
Ip was measured. The mean level of
Ip, shown in Fig. 2, was similar to the mean
level of myocytes exposed to ANG II in the superfusate only or to
RACK in pipette solution only.
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DISCUSSION |
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ANG II induces translocation in cardiac and noncardiac cells of
the classical PKC-, PKC
2-, and PKC
-isoforms
(4, 13, 27), the novel PKC
-isoform (13, 18, 22,
23, 25, 27), and the atypical PKC
-isoform (15,
27). The ANG II-induced decrease in Ip is
blocked by 20 nM staurosporine (10) and mimicked by
exposure of myocytes to phorbol 12-myristate 13-acetate (PMA) (1,
10). Staurosporine, in a concentration of 20 nM, has little if
any effect on PKC
(9), and PMA does not activate atypical PKC isozymes (3, 9). The
Ca2+-dependent
-,
2-, and
-isozymes
may be blocked under the conditions of the present study. These
considerations do not rule out a role for the
Ca2+-dependent isozymes or PKC
in mediating the ANG
II-induced decrease in Ip. However, in
combination with reports indicating that ACE inhibitors and ANG II
receptor antagonists prevent translocation of PKC
in the heart
(17, 23, 26), other researchers sought to justify a focus
on PKC
in search of a specific isozyme regulating the
Na+-K+ pump.
We used peptides that interfere with translocation of PKC. Upon
activation, PKC is translocated from binding sites in the cytoplasm to
isozyme-specific receptors for activated kinase (RACK). Peptides that
mimic the binding sites on RACKs or PKC prevent translocation and
inhibit kinase activity (see Refs. 3 and 19 for
review). To introduce a PKC-blocking peptide into the intracellular
compartment, we included the peptide in the patch pipette solution. For
the volume of rabbit myocytes (6) used, equilibration of a
molecule the size of the peptide is expected to be completed in the 4 min that elapsed from the time the whole cell configuration was
established until myocytes were exposed to ANG II (calculated according
to Ref. 24). The PKC
-blocking peptide in the
concentration we used or in a lower estimated intracellular concentration completely blocked translocation and activation of PKC
(12) in cardiac myocytes and functional responses mediated by the isozyme (7, 12, 16). We also examined the effect of
RACK, a peptide designed to bind to cytosolic isozyme-specific anchoring proteins, displace PKC, and cause its translocation to RACKs
(7). The peptide, in a concentration lower than that which
we used, induced translocation of PKC
in cardiac myocytes similar to
the translocation induced by the robust stimulus of 100 nM PMA
(7).
PKC-blocking peptide and
RACK are highly specific for
inhibiting (12, 32) and activating (7)
PKC
. The effect of the blocking peptide shows that activation of
PKC
is necessary for ANG II to induce a decrease in
Ip, and the effect of
RACK shows that
activation of PKC
is sufficient to induce a decrease in
Ip without concomitant activation of ANG II
receptors. If ANG II receptors and PKC
were linked to the
Na+-K+ pump via separate pathways, there might
be an additive effect of ANG II and activation of PKC
on
Ip. There was no such additive effect (Fig.
2). In general, stimuli initiate activation and interaction of
multiple cellular messengers in a complex "network" of pathways (see Refs. 2 and 20 for review). The present study
does not rule out participation of PKC isozymes other than PKC
or
other cellular messengers in the pathways controlling the sarcolemmal Na+-K+ pump. However, it has established that
PKC
is likely to play an important role.
The effect of PKC on the Na+-K+ pump has been extensively studied (see Ref. 30 for recent comprehensive review). The isolated, purified enzymatic equivalent of the Na+-K+ pump, Na+-K+-ATPase, can be phosphorylated at specific amino acid residues by PKC in vitro, and phorbol ester-induced activation of PKC in intact cells is associated with phosphorylation of Na+-K+ pumps in intact cells. It is tempting to assume that PKC-dependent regulation of the pump is a direct consequence of phosphorylation of the pump molecule. However, this assumption is not universally supported (see Ref. 30 for discussion).
There are also serious discrepancies between studies regarding the effect of PKC on the function of the Na+-K+ pump. Stimulation, inhibition, and the absence of any effect have been reported. A variety of different tissues have been studied; phorbol esters or diacylglycerol analogs have been used to activate PKC, and pharmacological blockers with no isoform specificity have been used to inhibit PKC. Tissue-dependent expression of PKC isoforms and isoform-specific response to experimental stimulation and inhibition may have contributed to the controversy regarding regulation of the pump by PKC. Isoform specificity should be taken into account when studying the effect of PKC on the Na+-K+ pump (30).
The mechanisms proposed for the effect of PKC on the pump vary widely. For studies reporting a PKC-induced decrease in pump activity, the mechanisms include internalization of Na+-K+ pumps and a change in the pump's apparent affinity for Na+ (30). A decrease in Ip secondary to internalization of pump units should be independent of the compositions of pipette solutions. However, a PKC-induced internalization of pumps is unlikely since the decrease in Ip depends on the presence of K+ in the solutions at the time Ip is measured (1).
We have previously shown that the dependence of the ANG II-induced
decrease in Ip on intracellular K+
suggests regulation of competitive inhibition by K+ of pump
activation by Na+ at sites near the cytoplasmic surface.
This K+/Na+ antagonism effectively contributes
to regulation of the apparent affinity of the pump for Na+
(1). The effect of PKC on this antagonism may not be
detected experimentally unless the intracellular Na+
concentration is carefully controlled at nonsaturating levels and
intracellular K+ or K+ congeners are present.
This has not been taken into account in previous studies. The
inhibitory effect of K+ at cytosolic pump sites is
particularly pronounced in cardiac tissue and may be variable and
subject to regulation by some cellular component(s) (29).
The present study implicates PKC
as one such component.
Regulation of the Na+-K+ pump may interact with
PKC in the pathogenic cardiac disease processes. Overexpression of
PKC
(28) or of the
RACK peptide (21)
causes cardiac hypertrophy in transgenic animal models. Pump inhibition
induced by PKC
may contribute to the hypertrophic process, an effect
that may be amplified because an increase in the intracellular
Na+ concentration in cardiac myocytes induces translocation
of PKC
(8). Cause-effect relationships between
Na+-K+ pump inhibition, activation of PKC
,
and cardiac hypertrophy cannot be established at present. However, from
a therapeutic perspective, it may be important that ACE inhibitors and
ANG II receptor antagonists can prevent translocation of PKC
in the heart (17, 23, 26). They can also induce a pump-mediated decrease in intracellular Na+ levels (11).
These effects might interrupt a PKC
-Na+-K+
pump interaction that contributes to the complex network of stimuli causing hypertrophy. It is consistent with these speculations that ACE
inhibitors and ANG II receptor antagonists have considerable efficacy
in prevention and treatment of cardiac hypertrophy.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart Foundation of Australia Grant G96S 4589 and by the North Shore Heart Research Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Rasmussen, Dept. of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, New South Wales, Australia 2065 (E-mail: Helger{at}med.usyd.edu.au).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1 August 2000; accepted in final form 6 April 2001.
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