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Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina 27599
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The aims of this study were to
determine whether preconditioning blocks cardiocyte apoptosis
and to determine the role of mitochondrial ATP-sensitive K+
(KATP) channels and the protein kinase C 
-isoform
(PKC-) in this effect. Ventricular myocytes from 10-day-old chick
embryos were used. In the control series, 10 h of simulated
ischemia followed by 12 h of reoxygenation resulted in
42 ± 3% apoptosis (n = 8). These results
were consistent with DNA laddering and TdT-mediated dUTP nick-end
labeling (TUNEL) assay. Preconditioning, elicited with three cycles of
1 min of ischemia separated by 5 min of reoxygenation before
subjection to prolonged simulated ischemia, markedly attenuated the apoptotic process (28 ± 4%, n = 8). The
selective mitochondrial KATP channel opener diazoxide (400 µmol/l), given before ischemia, mimicked preconditioning effects to
prevent apoptosis (22 ± 4%, n = 6). Pretreatment with 5-hydroxydecanoate (100 µmol/l), a
selective mitochondrial KATP channel blocker, abolished
preconditioning (42 ± 2%, n = 6). In addition,
the effects of preconditioning and diazoxide were blocked with the
specific PKC inhibitors Gö-6976 (0.1 µmol/l) or chelerythrine
(4 µmol/l), given at simulated ischemia and reoxygenation.
Furthermore, preconditioning and diazoxide selectively activated
PKC- in the particulate fraction before simulated ischemia
without effect on the total fraction, cytosolic fraction, and PKC
-isoform. The specific PKC activator phorbol 12-myristate 13-acetate
(0.2 µmol/l), added during simulated ischemia and
reoxygenation, mimicked preconditioning to block apoptosis. Opening mitochondrial KATP channels blocks cardiocyte
apoptosis via activating PKC- in cultured ventricular
myocytes. Through this signal transduction, preconditioning blocks
apoptosis and preserves cardiac function in
ischemia-reperfusion.
protein kinase C -isoform; mitochondrial ATP-sensitive potassium
channels
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CARDIOCYTE APOPTOSIS, or programmed cell death, is important in the pathogenesis of ischemic heart disease (7, 10, 16, 21, 28). Apoptotic cells are prominent in the border zone of an ischemic area (10) and have been documented in acute human myocardial infarction (32). Death of heart muscle results in an irreversible decrease in cardiac function, which correlates with overall morbidity and mortality in many clinical settings (6, 34). Because adult cardiocytes are postmitotic, damaged heart muscle cannot be regenerated through cell division. For these reasons, blocking cardiocyte apoptosis and identifying possible opportunities for intervention have significant clinical implications.
Transient ischemia, known as preconditioning, protects hearts against sustained ischemia and preserves cardiac function (24). This phenomenon, first described in 1986 (24), protects all species including humans (5, 29). Whether preconditioning blocks cardiocyte apoptosis is not established. We wanted to first determine whether preconditioning blocks apoptosis in a cardiocyte model of simulated ischemia-reoxygenation.
ATP-sensitive K+ channels (KATP) were discovered in cardiomyocytes in 1983 (25). The channels exist in the inner membrane of mitochondria (15) and mediate preconditioning to protect ischemic hearts (11, 12). How the channels mediate cardioprotection is not clear. We tried to determine whether the selective mitochondrial KATP channel opener diazoxide (8) could mimic preconditioning to attenuate apoptosis. We also used the channel antagonist 5-hydroxydecanoate (5-HD) (26) to try to abolish the effects of preconditioning on apoptosis.
Preconditioning also limits myocardial necrosis through protein kinase
C (PKC) activation (19, 30). PKC- and - seem more
important than other isoforms in this process (30). In vivo studies (23, 27) have suggested that preconditioning may block cardiocyte apoptosis via PKC activation. We
hypothesized that opening mitochondrial KATP channels
increases PKC- activity by which preconditioning attenuates
apoptosis in ischemia-reperfusion. Therefore, we
determined the effects of preconditioning and the KATP
channel opener diazoxide on enzyme activity of total PKC and the PKC
-isoform and on cardiocyte apoptosis.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cardiomyocyte Preparation
Ten-day-old embryonic chick ventricular myocytes were prepared using a method described by Barry et al. (2) and modified by Vanden Hoek et al. (35). Briefly, hearts were harvested and placed in Hank's balanced salt solution lacking magnesium and calcium (Life Technologies; Grand Island, NY). Ventricles were minced and myocytes were dissociated using four to six repetitions of trypsin (0.025%, Life Technologies) degradation at 37°C with gentle agitation. Isolated cells were then transferred to a solution with trypsin inhibitor for 8 min, filtered through a 100-µm mesh, centrifuged for 5 min at 1,200 rpm at 4°C, and finally resuspended in a nutritive medium described in our previous report (22a). Resuspended cells were placed in a petri dish in a humidified incubator (5% CO2-95% air at 37°C) for 45 min to promote early adherence of fibroblasts. Nonadherent cells were counted with a hemacytometer, and viability was measured using trypan blue (0.4%). Approximately 1 × 106 cells in nutritive medium were pipetted onto coverslips (25 mm) and incubated for 3-4 days, after which synchronous contractions of the monolayer were noted.Myocyte culture was checked for nonmuscle cell contamination by staining with anti-myosin heavy chain monoclonal antibodies (CCM-52) labeled by horseradish peroxidase. Coverslips with >95% of plated cells stained for myosin were used for our studies.
Experiments were performed on spontaneously contracting cells at days 3 or 4 after isolation. There were ~600 cardiomyocytes under the selected field for each experiment. Multiple fields were examined and compared before each study; the field with normal synchronous contraction was chosen and monitored throughout experiments.
Simulated Ischemia-Reperfusion System
A simulated ischemia solution (22a) was bubbled with a gas mixture of 20% CO2-80% N2 for 0.5 h before the experiments. The reperfusion solution was RPMI-1640 (GIBCO-BRL) without serum. During ischemia, cardiomyocytes on dishes filled with ischemia solution were placed into a hypoxic chamber at 37°C, where the low oxygen pressure was confirmed with an oxygen probe (pressure of O2 <1%). The cells in reperfusion media were incubated at 37°C with 5% CO2. The pH of the perfusion solution was routinely verified (simulated ischemic BSS, 6.8; RPMI-1640, 7.4).Multiple Assays for Cardiocyte Apoptosis
Flow cytometry. After treatment, cells were washed once with phosphate buffer solution (pH 7.4) and digested from the coverslip by enzymes (0.5 mg/ml collagenase IA and 0.025% trypsin, Sigma; St. Louis, MO) for 10-15 min at 37°C. The digestion was stopped by 10% serum. After centrifugation of 5 min at 1,300 rpm, cells were resuspended in staining solution with 50 µg/ml propidium iodide (PI; Molecular Probes; Eugene, OR), 0.5% Triton X-100, and 0.1% sodium citrate. After 12 h of staining, DNA fragmentation was quantified by flow cytometry. A wavelength of 670 nm (FL3-H) was used to detect the fluorescence intensity of PI with flow cytometry to quantify DNA fragmentation. The y-axis is the number of cells counted (labeled as "count"). The x-axis is the DNA size and content for each cell registered (labeled as "FL3-H"). Cells with normal DNA will have higher fluorescence intensity (see the peak in Fig. 2A). Apoptotic cells, which have more fragmented DNA, will have lower fluorescence intensity. The M region (left side of normal peak) is apoptotic. The number of cells in the M region divided by the total cell count is expressed as the percentage of apoptosis.
DNA laddering electrophoresis. The genomic DNA samples were purified by the phenol-chloroform extraction method (31). The DNA sample (0.5 µg) was loaded to 1.5% agarose and fractioned by electrophoresis.
In situ detection of apoptosis by TdT-mediated dUTP nick-end labeling staining. TdT-mediated dUTP nick-end labeling (TUNEL) staining of myocytes on the coverslip was performed according to the Trevigen TdT-Blue Label apoptosis detection kit (Trevigen; Gaithersburg, MD).
PKC enzyme assay.
The enzyme activity of total PKC and the PKC -isoform was measured
by a method described previously (9, 30). Briefly, 5 million cells for each experiment were collected in sample buffer [50
mmol/l Tris · HCl (pH 7.5), 5 mmol/l EDTA, 10 mmol/l EGTA, 10 mmol/l benzamidine, 50 µg/ml phenylmethylsulfonyl fluoride (PMSF), 10 µg/ml aprotinin, 10 µg/ml leupeptin, 10 µg/ml pepstatin A, and
0.3% 
-mercaptoethanol; Sigma]. The collection was centrifuged at
45,000 g for 30 min and separated into the cytosolic and
particulate fractions. The particulate pellet was dissolved
ultrasonically in sample buffer. Protein concentration was determined
with the Bradford method (4). Fifty to one hundred
micrograms of each fraction were assayed for total PKC and PKC-
activity using a kit (Amersham Pharmacia; Piscataway, NJ). For the
PKC- assay, the protein was immunoprecipitated overnight by PKC-
mAb (BD Transduction Lab) in immunoprecipitation buffer (pH 7.4) (150 mM NaCl, 50 mM Tris, 1 mM EGTA, 1 mM EDTA, 1% NP-40, 1 mM sodium orthovanadate, 1 mM PMSF, 16 µg/ml benzamidine-HCl, 10 µg/ml
phenanthroline, 10 µg/ml aprotinin, 10 µg/ml leupeptin, and 10 µg/ml pepstatin A; Sigma) with protein A/G beads (Santa Cruz
Biotech). In addition, a PKC--specific substrate (ERMRPRKRQGSVRRRV)
(BioMol; Plymouth Meeting, PA) was used for phosphorylation reaction
with [32P]ATP (Amersham Pharmacia). This substrate is
relatively specific for the PKC -isoform; however, it could be
phosphorylated by PKC- and other isoforms of PKC when the enzyme
activity of these isoforms is extremely high.
-soform were determined to ensure that the PKC enzyme assay worked properly.
Chemicals
Phorbol 12-myristate 13-acetate (PMA), 5-HD, diazoxide, chelerythrine, collagenase IA, trypsin, proteinase K, RNase, 2-deoxyglucose, and phenol-chloroform were purchased from Sigma. Gö-6976 was purchased from Calbiochem-Novabiochem (San Diego, CA). PMA and Gö-6976 were dissolved in BSS buffer before administration. PI was purchased from Molecular Probes.Statistical Analysis
Data are expressed as means ± SE. Differences between groups for cell death and enzyme activities were compared using a two-factor ANOVA with repeated measures and Fisher's least-significant-difference test. Differences between groups were considered significant if the P value was <0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Quantification of Apoptotic Cardiomyocytes
Figure 1 illustrates the experimental protocol. Ventricular myocytes from cultured chick embryos are widely used to define mechanisms of preconditioning (19, 22a, 35). With these cells, we established a reproducible methodology to quantify apoptosis by several complementary techniques (33). Staurosporin consistently induced 46% apoptosis (Fig. 2B, left) compared with only 8% in baseline controls (Fig. 2A, left). This result was consistent with DNA laddering electrophoresis (Fig. 2, A, bottom, and B, bottom). Myocyte culture was checked for nonmuscle cell contamination by staining with anti-myosin heavy chain monoclonal antibodies (CCM-52) labeled by horseradish peroxidase. More than 95% of plated cell stained for myosin (95.8 ± 1.02%, n = 5). TUNEL assay showed that apoptotic cells had condensed nucleoli (Fig. 2, A, right, and B, right). The quantitative results of counting TUNEL-positive nucleoli correlated well with those of flow cytometry. Counting of TUNEL-positive cells under the microscope with the naked eye has more "subjective" components; thus we only presented the percentage of cell death obtained with flow cytometry.
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Cardiocyte Apoptosis Was Attenuated by Ischemic Preconditioning
Ten hours of simulated ischemia and twelve hours of reoxygenation produced significant apoptosis (42 ± 3%, n = 8; Fig. 2C, left, right, and bottom). Preconditioning elicited by three cycles of simulated ischemia lasting 1 min separated by 5 min of reoxygenation produced significantly less apoptosis (28 ± 4%, n = 8; Fig. 2D, left, right, and bottom) compared with controls (Fig. 2C, left, right, and bottom) (P < 0.05).Role of PKC
Treatment with the specific PKC activator PMA (0.2 µmol/l) during ischemia-reperfusion blocked apoptosis to a similar degree as did preconditioning (32 ± 2%, n = 6; Fig. 2E, left, right, and bottom). The protection of preconditioning was blocked by specific PKC inhibition with Gö-6976 (0.1 µmol/l) or chelerythrine (4 µmol/l) added during ischemia-reperfusion (43 ± 2%, n = 6, and 39 ± 4%, n = 6; Fig. 3, C, left, right, and bottom, and E, left, right, and bottom). Gö-6976 and chelerythrine alone had no effects on ischemia-reperfusion injury (Fig. 3, B, left, right, and bottom, and D, left, right, and bottom). Thus preconditioning blocked apoptosis during ischemia-reperfusion via PKC activation.
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Role of Mitochondrial KATP Channels
Pretreatment with 5-HD (500 µmol/l), a selective mitochondrial KATP channel blocker (13, 26), reversed the effects of preconditioning (42 ± 2%, n = 6; Fig. 4C, left, right, and bottom). Transient administration of diazoxide (400 µmol/l), a selective mitochondrial KATP channel agonist (8), mimicked preconditioning and blocked apopotosis (22 ± 4%, n = 6; Fig. 4D, left, right, and bottom). These results indicate that mitochondrial KATP channel activation mediates preconditioning.
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Opening Mitochondrial KATP Channels Activates
PKC-
enzyme activities in the particulate fraction
(35.3 ± 2.6, n = 4, and 27.5 ± 1.9, n = 5, respectively, vs. 13.6 ± 2.1 pmol · min
1 · mg protein1,
n = 7, in baseline controls). Increased activity by
preconditioning was markedly attenuated by pretreatment with the
selective mitochondrial KATP channel blocker 5-HD (Fig.
5B). There was no difference in cytosolic PKC- enzyme
activity (Fig. 5B) and in total PKC enzyme activity (Fig.
5A) among all interventions.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Mitochondrial KATP channel activation mediates
preconditioning, the heart's own defense in an ischemic
attack, to reduce ischemia-reperfusion injury (11,
12). Mitochondria and mitochondrial KATP channels have an important function in modulating programmed cardiomyocyte death
in ischemia-reperfusion. Opening of the channels mimics the
effects of preconditioning to block cardiocyte apoptosis via activation of the PKC -isoform.
Apoptosis, known as programmed cell death, is modulated and controlled by multiple cellular genes (21). The apoptotic process has many important roles in cell development, tissue differentiation, and the pathogenesis of ischemic heart disease (7, 16, 32). The caspase enzyme family (caspase-3) initiates apoptosis in heart tissue after exposure to ischemia-reperfusion (3). Characteristic changes of apoptotic cells include shrinkage, organelle condensation, genome DNA degradation, and membrane breakage. Phosphatidyl serine residues flip from the interior of the plasma membrane to the exterior, and the cell blebs to form apoptotic bodies, which are then phagocytosed and cleared without agitating an inflammatory response. DNA fragmentation is one of classical hallmarks of apoptosis (33).
Our results agree with those of others who found significant apoptosis in rabbit ischemic-reperfused hearts (7, 10) and in human acutely infarcted myocardium (28, 32). The mechanism by which ischemia and reperfusion induce apoptosis is unknown. A marked increase in the activity of caspase-3 was noticed during simulated ischemia. This suggests that caspase-3 is important in initiation of cardiocyte apoptosis during ischemia-reperfusion. Obviously, more experiments are needed to examine the role of caspase-3 and other family members of caspases in the pathogenesis of myocardial ischemia-reperfusion injury. Interestingly, we noticed significantly less apoptosis after preconditioning compared with controls. Okamura and colleagues (27) have suggested that ischemic preconditioning attenuated apoptosis in intact rat hearts.
The protective effects of preconditioning were abolished with 5-HD, a selective mitochondrial KATP channel blocker (13). Transient administration before ischemia of diazoxide, a selective mitochondrial KATP channel opener, mimicked preconditioning. Therefore, mitochondrial KATP channel activation blocks apoptosis, by which preconditioning occurs. These data also indicate that mitochondria and mitochondrial KATP channels have a crucial role in modulating programmed cardiomyocyte death.
KATP channels were discovered in cardiomyocytes in 1983 (25). The channels are found in the inner membrane of mitochondria (15), and they mediate preconditioning to reduce myocardial necrosis in anesthetized rats and dogs (11, 12) and in isolated rabbit cardiomyocytes (1). With the use of a similar cardiocyte preparation from chick embryos, Liang (17) showed that the channel opener pinacidil limited cell necrosis. Many substances, including adenosine, acetylcholine, and opioids, protect against ischemia-reperfusion injury via opening of the channel (12, 30). The downstream mechanism by which the channel protects ischemic hearts is still puzzling.
The channel opener diazoxide and preconditioning markedly increased PKC
-isoform enzyme activity in the particulate fraction (but not the
cytosolic fraction). Ping and co-workers (30) also found that preconditioning enhanced redistribution of the PKC -isoform to the particulate fraction and reduced myocardial necrosis in conscious rabbits. The protection of preconditioning was blocked by
specific PKC inhibition with Gö-6976 or chelerythrine given during simulated ischemia-reoxygenation.
Gö-6976 has been shown to be a selective inhibitor for PKC 
-
and -isoforms at doses below the micromole per liter range
(22). The dose of Gö-6976 used for the present study
was 0.1 µmol/l. At the micromole per liter dose range, it is likely
that Gö-6976 looses its selectivity for PKC - and
-isoforms, thus blocking other isoforms of PKC. The specific PKC
activator PMA added during ischemia-reperfusion blocked
apoptosis. Preconditioning activated PKC to limit cardiocyte necrosis in vitro (19) and in vivo (30). One
in vivo study (27) suggested that preconditioning
attenuated apoptosis via PKC activation. Taken together, our
results suggest that mitochondrial KATP channel opening
modulates cardiocyte apoptosis through activation of the
particulate PKC -isoform without affecting total intracellular PKC
enzyme activity. Activated PKC- may further amplify the opening of
mitochondrial KATP channels and exert cardioprotection.
It is likely that the opening of mitochondrial KATP
channels activates the PKC -isoform through oxygen radicals
originating in mitochondria (22a). With the use of a similar
cardiomyocyte preparation, we (22a) and other investigators
(35) previously demonstrated that preconditioning produces
oxygen radicals and that mitochondria were the source of these
radicals. Mitochondrial KATP channel opening was important
in release of these radicals (22a). Oxygen radicals activate PKC
(9). Activated PKC- may be translocated to
mitochondria, where it attenuates apoptosis via regulation of
Ca2+ channels (14), KATP channels,
phosphorylation of numerous rate-limiting enzymes, or an increase of
gene expression (20, 37). However, there is no direct
evidence that PKC- phosphorylates the channels and rate-limiting enzymes.
The present results were obtained from cardiomyocytes of chick embryos. Fetal cardiomyocytes may behave differently from those of adult hearts. It should be cautious that our findings may not be the case in adult caridomyocytes or in in vivo models of cardiac ischemia-reperfusion. On the basis of our previous studies (20, 22a) and those of others (11, 12, 19), chick embryonic cardiomyocytes shared many common signaling pathways with those of adult hearts (18).
Finally, we want to emphasize that apoptosis and necrosis are two distinct process of cell death. Both contribute to loss of cardiac function during ischemia-reperfusion. At present, there are no specific tests for identifying and quantifying apoptosis. Cardiocyte necrosis can result in small changes in flow cytometry, TUNEL staining, DNA laddering, caspase activity, and other methods for apoptosis (33). In addition, KATP channel opening, PKC activation, and oxygen radicals also mediate preconditioning to limit necrosis. The KATP channel opener pinacidil reduced cell necrosis from ischemia-reperfusion (1, 17). In this study, cardiocyte apoptosis is analyzed with three complementary methods, so we are confident that preconditioning attenuates apoptosis during ischemia-reperfusion.
In conclusion, the results of this study indicate that mitochondrial
KATP channel opening generates oxygen radicals that
activate the particulate PKC -isoform. Through this signaling
pathway, preconditioning blocks cardiocyte apoptosis and
preserves cardiac function during ischemia-reperfusion. The
present data also suggest that mitochondria and mitochondrial
KATP channels have important function in modulating
cardiomyocyte apoptosis.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-03881, HL-70324, and HL-70325.
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FOOTNOTES |
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10.1152/ajpheart.00348.2001
Address for reprint requests and other correspondence: Z. Yao, Dept. of Anesthesiology, Univ. of North Carolina at Chapel Hill, 223 Burnett-Womack Bldg., CB7010, Chapel Hill, NC 27599-7010 (E-mail: zyao{at}aims.unc.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.
Received 27 April 2001; accepted in final form 20 November 2001.
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METHODS
RESULTS
DISCUSSION
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