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signaling pathway
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0529
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Protein kinase C (PKC) plays a central
role in both early and late preconditioning (PC) but its association
with inducible nitric oxide synthase (iNOS) is not clear in late PC.
This study investigates the PKC signaling pathway in the late PC
induced by activation of adenosine A1 receptor
(A1R) with adenosine agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and the
effect on iNOS upregulation. Adult male mice were pretreated with
saline or CCPA (100 µg/kg iv) or CCPA (100 µg/kg iv) with PKC-
inhibitor rottlerin (50 µg/kg ip). Twenty-four hours later, the
hearts were isolated and perfused in the Langendorff mode. Hearts were
subjected to 40 min of ischemia, followed by 30 min
reperfusion. After ischemia, the left ventricular end-diastolic
pressure (LVEDP) was significantly improved and the rate-pressure
product (RPP) was significantly higher in the CCPA group compared with
the ischemia-reperfusion (I/R) control group. Creatine kinase
release and infarct size were significantly lower in the CCPA group
compared with the I/R control group. These salutary effects of CCPA
were abolished in hearts pretreated with rottlerin. Immunoblotting of
PKC showed that PKC- was upregulated (150.0 ± 11.4% of
control group) whereas other PKC isoforms remained unchanged, and iNOS
was also significantly increased (146.2 ± 9.0%,
P < 0.05 vs. control group) after 24 h of
treatment with CCPA. The data show that PKC is an important component
of PC with adenosine agonist. It is concluded that activation of
A1R induces late PC via PKC- and iNOS signaling pathways.
ischemia; myocardial infarction; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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LATE PRECONDITIONING
(PC) can be elicited by sublethal ischemia (19,
23) or various pharmacological treatments including activation
of adenosine A1 (1, 2, 7), A3
(18, 25), and opioid 1-receptors
(10), or diazoxide (31). Transient activation
of adenosine A1 receptor (A1R) induces late PC
against myocardial infarction and stunning. However, it is not known
whether the downstream events following adenosine-induced late PC have a mechanism similar to those in the early PC. Protein kinase C (PKC)
isoforms, PKC- and -
are primarily described to be responsible for activating the mediators in PC. PKC- is an especially important central mediator in ischemic PC (12, 24, 32).
However, Kawamura et al. (16) suggested that in addition
to PKC-, the -isoform is also translocated to the membrane
fraction after ischemic PC and is involved in the development
of protection against postischemic left ventricular (LV)
dysfunction. PKC- is activated and transported to mitochondria
perinuclear sites, and PKC- is translocated to the intercalated
disk, sarcomeric proteins in early PC induced by Ca2+
(23), diazoxide (30, 31), or opioid
1-receptor (11). Cardioprotection was
abolished by rottlerin, a PKC--specific inhibitor. Moreover,
rottlerin blocks the development of diazoxide-induced late PC
(26, 31). Furthermore, in neonatal cardiocytes, expression of active PKC- increases resistance to simulated ischemia
(34). Thus there is much controversy regarding the role
and function of these isoforms in the phenomenon of PC. Inducible
nitric oxide (NO) synthase (iNOS) is a common mediator of the
cardioprotective effects of late PC induced by different triggers
(5, 14), including late PC by activation of
A1R (25, 35), opioid
1-receptors (10), NO donors, and
diazoxide (31). However, other investigators (4,
6) have concluded that iNOS does not play a necessary role in
A1R-induced late PC (4, 6). Thus it is a point
of a dispute whether effect of A1R-induced PC depends on
iNOS. We determined the role of PKC- and iNOS in mediating
A1R-induced delayed PC using the PKC--specific inhibitor rottlerin.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Adult male mice (FVBN strain; 25-30 g body wt) were supplied by Harlan Sprague Dawley. Standard rodent food and water was freely accessible. All animal experiments were conducted under the guidelines on human use and Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85-23, Revised 1996).
Drugs and chemicals. 2-Chloro-N6-cyclopentyladenosine (CCPA) and anti-iNOS antibody were purchased from Calbiochem. Triphenyltetrazolium chloride was purchased from Sigma. The anti-PKC primary antibodies were purchased from Santa Cruz Biotechnology. Anti-rabbit IgG alkaline phosphatase conjugated antibody was purchased from KPL.
Langendorff-perfused isolated heart preparation. Animals were anesthetized with pentobarbital sodium (40 mg/kg ip) and heparinized (5,000 U/kg) to protect the heart against microthrombi. The chest was opened at the sternum and the heart was quickly removed and was then cannulated with a 20-gauge phalanged stainless steel cannula. Hearts were retrogradely perfused through the aorta in a noncirculating Langendorff apparatus with Krebs-Henseleit (KH) buffer, which consisted of (in mM) 118 NaCl, 4.7 KCl, 1.2 MgSO4, 1.2 KH2PO4, 2.5 CaCl2, 25 NaHCO3, 0.5 Na-EDTA, and 11 glucose. The buffer was saturated with 95% O2-5% CO2 (pH 7.4, 37°C) for 50 min. Hearts were perfused at a constant pressure of 80 mmHg. A homemade water-filled balloon was inserted into the left ventricle through the left atrium and was inflated to adjust the LV end-diastolic pressure (LVEDP) to 5-10 mmHg during initial equilibration. Thereafter, the balloon volume was not changed. The distal end of the catheter was connected to a Digi-Med Heart Performance Analyzer (model 210, version 1.01, Micro-Med) via a pressure transducer (Case; Lakewood, CO). The index of myocardial function was determined as previously described (30). Hearts were perfused with the oxygenated Krebs-Henseleit buffer for a total of 95 min (37°C), consisting of a 25-min preischemic period, followed by 40 min of global ischemia and 30 min of reperfusion. Myocardial ischemia injury was correlated with the infarct size, creatine kinase (CK) release, LV developed pressure (LVDP), LVEDP, and the rate-pressure product.
Ischemia-reperfusion protocol.
Adult male mice were pretreated with saline or CCPA (100 µg/kg iv) or
CCPA (100 µg/kg iv) with the PKC- inhibitor rottlerin (50 µg/kg
ip) (11, 31) (IC50 = 3-6 µM).
Twenty-four hours later, the hearts were isolated and perfused in the
Langendorff mode. After a 25-min equilibration period, hearts were
subjected to 40 min of no-flow normothermic global ischemia and
30 min of reperfusion. Four experimental groups were used in this
study, as shown in Fig. 1.
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Measurement of CK release.
CK, an indicator of myocardial tissue injury, was determined in the
coronary effluent by a coupled enzyme spectrometric technique using a
Sigma assay kit (Catalog No. 1340-K). CK was measured at 3, 5, 10, 20, and 30 min of reperfusion. CK in the coronary effluent was calculated
(30) as the amount released per minute per gram of heart
weight [CK (U/ml) × coronary flow (CF) (ml/min)/heart weight
(g) = U · min
1 · g1].
Measurement of infarct size. At the end of I/R, 1% of triphenyltetrazolium chloride solution was injected down the side arm of the aortic cannula and infused into the coronary circulation. Once the hearts were stained dark red, they were removed, weighed, and frozen. The following day, they were defrosted, sliced into 1-mm sections parallel to the atrioventricular groove, and then fixed in 10% buffered formalin overnight. The image of slice was scanned with flatbed scanner and the area of infarction and total ventricular zone were planimetered with the use of image analysis software (NIH Image).
Protein extraction and Western immunoblot analysis.
For the measurement of total PKCs, hearts were weighed and homogenized
at 4°C in 1-ml RIPA buffer containing 10 mM Tris · HCl, pH
7.4, 150 mM NaCl, 0.1 mM EDTA, 10 µg/ml aprotinin, 10 µg/ml
leupeptin, 50 mM NaF, 1 mM Na3VO4, 1 mM
dithiothreitol, 4 mM Pefabloc SC, and 1% Nonidet P-40, with the use of
a Polytron TP-20. Homogenates were then centrifuged at 26,000 g at 4°C for 30 min to collect the supernatant. Protein
concentration of samples were determined by DC protein assay (Bio-Rad),
and the equal amount of protein of each samples was loaded and run on a
8% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and were
electrophoretically transferred onto a polyvinylidene fluoride membrane
(Millipore; Bedford, MA). After verification of the amount of protein
in each lane with Ponceau S staining, blots were blocked for 1 h
with 5% dried milk in Tris-buffered saline containing 0.2 M
Tris · HCl, 150 mM NaCl, and 0.01% Tween 20, and subsequently
incubated overnight at 4°C with a 1:1,000 dilution of anti-PKC-,
anti-PKC-, or anti-iNOS antibody. After 30 min of being washed with
Tris-buffered saline, blots were incubated with 1:2,000 dilution of
alkaline phosphatase-conjugated secondary antibody for 1 h at room
temperature. Immunoreaction products were visualized using
p-nitroblue tetrazolium chloride 5-bromo-4-chloro-3-indolyl
phosphate, the resultant bands were quantified using NIH image
software, and these data were statistically analyzed.
Statistical analysis. All values were expressed as means ± SE. Group comparisons were analyzed by one-way analysis of variance (ANOVA, Statview version 4.0). All groups were analyzed simultaneously with a Bonferroni-Dunn test. A difference of P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Cardiac function.
LVEDP, LVDP, CF, and heart rate were recorded in all groups. In
addition, we calculated the rate-pressure product (LVDP × heart
rate/1,000) as an index of oxygen demand. CCPA, rottlerin, and dimethyl
sulfoxide treatments did not influence the hemodynamic parameters
during equilibration. LVEDP remained at a high level during
reperfusion in the ischemic control group compared with the
CCPA-treated group (Fig. 2A).
Rottlerin attenuated the effects of CCPA (Fig. 2A). CF was
reduced during the reperfusion in the control group (Fig.
2B). CCPA tended to increase CF compared with control group
during reperfusion. Rottlerin attenuated the effects of CCPA (Fig.
2B). Rate-pressure products were increased in hearts pretreated with CCPA and the protective effect of CCPA was attenuated with rottlerin (Fig. 2C).
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Release of CK.
At 3, 5, 10, 20, and 30 min of reperfusion after global
ischemia, release of CK into coronary effluent was measured
(Fig. 3). At 10, 20, and 30 min of
reperfusion, release of CK from the control heart was 7.12 ± 0.42, 4.71 ± 1.70, and 3.51 ± 1.90 U · min1 · g1,
respectively. However, CCPA treatment significantly decreased the
release of CK compared with the ischemic control group, whereas rottlerin attenuated the effects of CCPA.
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Myocardial infarct size.
Myocardial infarct size was 34.6 ± 3.8% of the risk zone in the
control ischemia group (Fig. 4).
In the CCPA group, infarct size was significantly reduced (18.9 ± 2.3%, P < 0.05 vs. control group). Furthermore,
rottlerin blocked the protective effect of CCPA (31.4 ± 4.2%)
(Fig. 4).
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Effect of CCPA on the expression of PKC isoforms and iNOS.
After 24 h of CCPA pretreatment, PKC- was increased to
150.0 ± 11.4% of control group, and rottlerin suppressed the
effect of CCPA (104.2 ± 11.5%). There was no significant
expression of PKC- in any other groups (Fig.
5). Furthermore, CCPA increased iNOS
synthesis (146.2 ± 9.0%, P < 0.05 vs. control
group) and rottlerin blocked the effect of CCPA on iNOS synthesis
(90.5 ± 8.6%) (Fig. 6).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The mechanism of A1R-induced late PC remains unclear
and is the focus of the current investigation. The present study
demonstrates that the tolerance to ischemic injury was
increased 24 h after transient activation of A1R with
CCPA. We observed a significant protection against myocardial
infarction 24 h after treatment with the selective A1R
agonist CCPA, and it was abolished by inhibition of PKC- with the
specific inhibitor rottlerin. In addition, PKC- was upregulated
24 h after treatment with CCPA and this was also abolished when
mice were pretreated with rottlerin. Furthermore, the present study
demonstrated that the synthesis of iNOS was increased 24 h after
transient activation of A1R, and this increase was blocked
by rottlerin. These data point out the crucial role of PKC- and iNOS
in the signal transduction leading to A1R-induced delayed PC.
Cardiac function and infarct size.
Previous studies have shown that activation of A1R-induced
delayed protection against myocardial infarction in the rabbits (1, 9, 17, 18, 21, 25), rats (8), and mice
(35, 36). Kodani et al. (17, 18) and Takano
et al. (25) reported that the recovery of the systolic
wall thickening was improved in rabbits pretreated with CCPA. Zhao et
al. (35, 36) demonstrated that CCPA improved recovery of
LVEDP and rate-pressure product in mice. Furthermore, in early PC in
the rat isolated heart, Lozz et al. (20) demonstrated that
pretreatment with CCPA in rat heart decreased LVEDP and coronary
perfusion pressure and recovered LVDP after restoration of coronary
flow. The present study showed that CCPA attenuated the decrease of CF
and the increase of LVEDP. The rate-pressure product was improved
during reperfusion. In addition, the CK release was reduced and the
infarct size was decreased by CCPA treatment compared with control
group. Dana et al. (9) has shown that CCPA-induced delayed
protection was blocked by inhibition of either PKC or tyrosine kinases
(TKs), suggesting that both PKC and TKs are crucial for the development of delayed PC after A1R activation in the rabbit. Henry et
al. (13) reported that A1R stimulation
activated PKC- in isolated rat ventricular myocytes. Thus our data
suggest that activation of PKC- by A1R stimulation is an
important trigger in the signal transduction of CCPA-induced late PC.
Mechanistic involvement of PKC and iNOS protein in
A1R-induced protection.
Several studies (6, 25, 35) have shown that iNOS is an
obligatory mediator of late PC after stimulation of A1R. In contrast, other investigators (4, 7) reported that the
protection appears not to be iNOS dependent. The role of iNOS in the
A1R-induced late PC seems to be controversial. We
(31) have previously shown that NO was the trigger in the
diazoxide-induced-late PC, and prior inhibition of PKC- with
rottlerin blocked the nuclear translocation of nuclear factor (NF)-
B
resulting in the loss of cardioprotection. These results suggest that
the pathway of PKC--NF-B-iNOS is important in the induction of
late PC. Xuan et al. (33) demonstrated that
ischemic PC-induced isoform-selective activation of Janus kinase (JAK)1, JAK2, signal transducers and activators of transcription (STAT)1, and STAT3, and that ablation of this response impeded the
upregulation of iNOS and the acquisition of ischemic tolerance. These reports suggest that upregulation of iNOS requires activation of
NF-B or the JAK-STAT signaling pathway in late PC. It is likely that
iNOS upregulation is mediated by NF-B activation via the PKC-
signaling pathway in the A1R-induced late PC.
Other mediators and effectors.
A1R-induced late PC is dependent on the opening of
mitochondrial ATP-sensitive K+ (mitoKATP)
channels during the index ischemic insult (3). Zhao et al. (36) demonstrated that p38 mitogen-activated
protein kinase (MAPK) phosphorylation and mitoKATP channels
played a role in A1R-induced late PC. Dana et al.
(9) described that both PKC and TKs played an important
role as mediators of late PC against infarction after A1R
activation and pointed out the p38 MAPK/heat shock protein 27 pathways
as a potential distal effector. Induction and activation of manganese
superoxide dismutase is also believed to play a crucial role in
mediating delayed myocardial adaptation after A1R
activation (8). Previous studies (26,
29-31) showed that mitoKATP channel is the end
effector of both early and late PC. Diazoxide pretreatment
significantly increased nuclear translocation of NF-B, which was
blocked by the PKC--specific inhibitor rottlerin or
NG-nitro-L-arginine methyl ester, an
inhibitor of iNOS. This study concluded that diazoxide activated
NF-B via PKC signaling pathway and that leads to iNOS upregulation
after 24 h. Moreover, diazoxide was totally ineffective in iNOS
knockout mice, suggesting that NO is involved in opening of
mitoKATP channels. Zhao et al. (35) showed
recently that A1R activation upregulated iNOS expression and demonstrated that A1R-induced late PC was lacking in
the iNOS knockout mice. Therefore, it appears that mitoKATP
channels may be activated by NO as a result of iNOS upregulation by
A1R activation. Moreover, Wagner et al. (28)
described that adenosine induces the expression of interleukin-6 (IL-6)
through activation of the A3R and possibly the
A1R in the isolated cardiomyocytes. On the other hand,
PKC- specifically is associated with STAT3 in several cell types in
an IL-6-inducible manner (15). Therefore, the association
of PKC- and STAT3 by the adenosine-induced IL-6 is important for the
A1R-induced late PC.
signaling pathway. On the basis of our previous study, it is
likely that NO generation by iNOS is an important trigger for the
activation of mitoKATP channels, which is responsible for
the cardiac protection.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-23597 and HL-55678.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Ashraf, Dept. of Pathology and Laboratory Medicine, Univ. of Cincinnati Medical Center, 231 Bethesda Ave., Cincinnati, OH 45267-0529 (E-mail: Muhammad.Ashraf{at}UC.edu).
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.
10.1152/ajpheart.01087.2001
Received 11 December 2001; accepted in final form 18 January 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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