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* Department of Medicine, Cardiovascular Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA; and
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
1Correspondence: 956 BRBII/III, University of Pennsylvania Medical Center, 421 Curie Boulevard, Philadelphia, PA 19104, USA. E-mail: liangb{at}mail.med.upenn.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: ischemia • ventricular myocyte • PKC activity • cardioprotection
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Furthermore, adenosine released during a brief
ischemic episode is able to protect the heart against injury during a
subsequent period of prolonged ischemia, resulting in a reduction in
infarct size (2
3
4
5
6
7
8)
. Brief exposure of the heart to
adenosine, instead of to ischemia, induces a similar protective effect
against subsequent ischemia-induced damage. Although both
A1 and A3 subtypes of
adenosine receptors mediate cardioprotection, the respective protective
effects are distinct (9)
. The signaling mechanisms that
underlie these distinct receptor-mediated responses have remained
unknown.
A culture model for simulating ischemia and cardioprotection has been
developed with embryonic chick cardiac ventricular myocytes (5
, 9
, 10
, 11)
. This model exhibits adenosine-induced protective
effects similar to those apparent in the intact heart (4
, 6
7
8
, 12
, 13)
. With this cardiac cell model, the objective of the
current study was to investigate whether the signaling mechanism
underlying the adenosine A1 receptor-mediated
cardioprotective effect differs from that used by the adenosine
A3 receptor. Specifically, the study was aimed at
testing the hypothesis that the distinct cardioprotective effects were
mediated by differential coupling of adenosine A1
and A3 receptors to phospholipase C (PLC) and
phospholipase D (PLD), respectively.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 10)
. In simulating ischemia and ischemic preconditioning, the
medium was changed to a glucose-free HEPES-buffered medium containing
(mM) 139 NaCl, 4.7 KCl, 0.5 MgCl2, 0.9
CaCl2, 5 HEPES
(N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), and 2% fetal
bovine serum, pH=7.4, 37°C before exposing the cells to simulated
ischemia. Ischemia was simulated by incubating the myocytes in a
hypoxic incubator (NuAire) for 90 min, during which
O2 was replaced by N2 as
described previously (5
, 10)
. Determination of myocyte
injury was made at the end of the simulated ischemia, when aliquots of
the media were collected for creatine kinase activity measurement. This
was followed by quantitation of the number of viable cells. Measurement
of the basal level of cell injury was made after parallel incubation of
control cells under normal % (room air) O2. The
extent of ischemia-induced myocyte injury was quantitated as increased
number of cells killed and amount of creatine kinase (CK) released. The
amount of CK was measured as enzyme activity (unit/mg), and increases
in CK activity above the control level were determined. The percentage
of cells killed was calculated as the number of cells obtained from the
control group (representing cells not subjected to any hypoxia or drug
treatment) minus the number of cells from the treatment group divided
by the number of cells in the control group multiplied by 100%. The percentage of cells killed was determined as follows. Cells treated under the various conditions were allowed to recover at 37°C for 1 h before being sedimented at 300 g for 10 min. The pellet was then resuspended in 1 ml of the medium used to incubate cells during the preconditioning protocol. Resuspended cells were drawn up and placed in the hemocytometer for quantitation. The concentration of cells counted was then converted to the total number of cells in 1 ml. Two additional lines of evidence are provided to support the validity of the assay for quantitating cells injured. First, there was minimal variability of proteins from one culture plate to another (a typical culture has 0.9±0.03 mg protein per 60 mm dish, ± SD, n=20 dishes). The CK enzyme activity was then normalized to the total cellular protein (total amount of protein on the plate in the absence of ischemia or other experimental intervention). Second, parallel changes in percentage of cells killed and CK released during preconditioning by adenosine or by the brief hypoxia or during the various interventions further validated this assay for percentage of cells killed. Overall, the data indicate that the assay for quantitating percentage of cells killed can separate out hypoxia-damaged from control normoxia-exposed cells.
Preconditioning of the cardiac myocyte was achieved by exposing the
myocyte to either simulated ischemia or adenosine receptor agonist for
5 min as described previously (5
, 10)
. In preconditioning
induced by 5 min simulated ischemia, myocytes were then incubated under
an intervening normoxic condition before being exposed to 90 min of
simulated ischemia. In preconditioning induced by adenosine receptor
agonist, myocytes were incubated for 10 min with agonist-free medium,
and then exposed to simulated ischemia for 90 min. Myocytes not
subjected to preconditioning were exposed to 90 min ischemia only
(non-preconditioned cells).
Measurement of diacylglycerol level and determination of
phospholipase C, phospholipase D, and protein kinase C activity
Quantitation of diacylglycerol (DAG) was carried out as
described previously (14
, 16)
. In brief, cultured myocytes
were labeled with [3H] myristate (49 Ci/mmol, 2
µCi/ml) for 24 h and exposed to receptor agonist for the times
indicated. Lipids were extracted by the method of Bligh and Dyer
(17)
. The formation of [3H] DAG in
cells was quantitated by separation of the labeled DAG from other
phospholipids on thin-layer chromatography (petroleum
ether/diethylether/acetic acid, 70/30/1, v/v/v on a Whatman K6 Silica
Gel 60A plate) and scintillation counting of the
3H label in spots migrating to the same position
as unlabeled DAG. For measurement of PLD activity, myocytes labeled
with [3H] myristate for 24 h were exposed
to receptor agonist in the presence of 0.5% (v/v) ethanol. The
formation of [3H] phosphatidylethanol (PEt) was
determined by scintillation counting after its separation from other
phospholipids on thin-layer chromatography
(chloroform/methanol/H2O, 65/25/3, v/v/v on
the Whatman K6 Silica Gel 60A plate) as described (15
, 16)
. The level of [3H] PEt represents an
index of the PLD activity. The position of DAG or PEt was determined
visually by placing the thin layer plate in an iodine chamber, and
their levels were expressed as a percentage of total lipids. Data were
expressed as the percentage increase in the amount of DAG or PEt
relative to that for unstimulated cells.
The PLC activity was determined as the increase in the total inositol
phosphates after receptor agonist stimulation according to a previously
described method (19
, 20)
. Myocytes were labeled with
myo-[3H]inositol (21 Ci/mmol, 5
µCi/ml) for 24 h and stimulated for 30 min with the indicated
concentrations of receptor agonist. The sum of inositol 1-phosphate,
inositol 1,4-bisphosphates, and inositol 1, 4, 5-trisphosphate
represented the total inositol phosphates. Data were expressed as the
percentage increase in the amount of inositol phosphates relative to
that for unstimulated cells. Protein kinase C activity in the intact
myocyte was determined as described previously (21)
. In
brief, ventricular myocytes were labeled with carrier-free
[32P]orthophosphate (100 µCi/ml) for 4 h
and then incubated in the absence or presence of adenosine
A1 or A3 receptor agonist
for 10 min. The phosphorylation of the PKC substrate MARCKS
(myristoylated alanine-rich C kinase substrate) was then examined by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
autoradiography as described (21)
. The position of the 60
kDa MARCKS protein and of molecular size standards (in kilodaltons) are
indicated.
Gene transfer into cardiac myocytes
Cardiac atrial myocytes were transfected with pcDNA3 or the
recombinant pcDNA3 vector using a newly modified calcium phosphate
precipitates method (22)
. Human cDNAs encoding the
adenosine A3 receptor
(hA3R) were subcloned into the eukaryotic
expression vector pcDNA3, termed pcDNA3/hA3R.
Cardiac myocytes were maintained in culture for 24 h prior to
being exposed to the calcium phosphate/DNA precipitates for 6 h at
37°C. Media were replaced with fresh growth media and the myocytes
were cultured for an additional 48 h. The expression of human
adenosine A3 receptor cDNAs as functional
proteins was determined by the ability of transfected human adenosine
A3 receptor to mediate inhibition of
isoproterenol-stimulated adenylyl cyclase, as determined previously
(9
, 23)
.
Materials
The adenosine analog
2-chloro-N6-cyclopentyladenosine (CCPA), and the
protein kinase C inhibitor chelerythrine were from Research
Biochemicals International (Natick, Mass.). Cl-IB-MECA was synthesized
according to a previously described procedure (24)
. In
brief, methyl 1,2,3-tri-O-acetyl-ß-D-ribofuronate was condensed with
silylated 2-chloro-N6-(3-iodobenzyl)adenine in
dry 1,2-dichloroethane using trimethylsilyl triflate as a catalyst (2 h
at room temperature followed by 48 h reflux). The ß-anomer
(methyl
1-[2-chloro-N6-(3-iodobenzyl)-adenin-9-yl]-2,3-di-O-ß-D-ribofuronate)
was isolated using silica gel column chromatography and treated with
methylamine in THF overnight at 50°C in a sealed tube to provide
Cl-IB-MECA (methyl
1-[2-chloro-N6-(3-iodobenzyl)-adenin-9-yl]-ß-D-ribofuronamide).
1-(6-((17ß-3-methoxyestra-1,3,5
(10)
-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
(U-73122) was obtained from BioMol (Plymouth Meeting, Pa.).
Diacylglycerol and phosphatidylethanol were from Avanti Polar Lipids
(Alabaster, Ala.). Propranolol was obtained from Sigma Chemical Co.
(St. Louis, Mo.). The vector pcDNA3 was obtained from Invitrogen
(Carlsbad, Calif.). [3H]myristate,
myo-[3H]inositol,
[32P]orthophosphate were from New England
Nuclear (Boston, Mass.). Embryonated chick eggs were from Spafas, Inc.
(Storrs, Conn.).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Since this effect of adenosine is mediated by its
receptors, the objective here was to determine whether a PKC inhibitor
could block the cardioprotective effect induced by adenosine
A1 receptor- or A3
receptor-selective agonists. Figure 1A
shows that chelerythrine abolished the
preconditioning-like effect of an A1 (CCPA,
2-chloro-N6-cyclopentyladenosine) or
A3 (Cl-IB-MECA,
2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide)
receptor agonist, indicating that PKC acts downstream from each
receptor in mediating this effect. The link between adenosine receptors
and PKC was further supported by the observation that activation of
either A1 or A3 receptors
induced both accumulation of the PKC activator DAG (Fig. 1B
)
and PKC activation itself (Fig. 1C
) in intact myocytes.
However, the effect of the A3 receptor agonist
Cl-IB-MECA on the abundance of DAG was more pronounced and longer
lasting than that of the A1 receptor agonist
CCPA. Because PLD stimulation produces a more sustained increase in DAG
level, these data suggested that the A3 receptor
is coupled to PLD, whereas the A1 receptor is
coupled to PLC.
|
Coupling of the adenosine A1 receptor to PLC and of the
adenosine A3 receptor to PLD
The coupling of each receptor subtype to these phospholipases was
investigated directly by measuring the effects of the selective
agonists on the production of both inositol phosphates (products of
PLC-mediated hydrolysis of inositol phospholipids) and
phosphatidylethanol (a product of PLD-mediated hydrolysis of
phospholipids in the presence of ethanol). The A1
receptor agonist CCPA induced a markedly greater increase in the
production of inositol phosphates than did the A3
receptor agonist Cl-IB-MECA (Fig. 2A
), whereas the increase in PEt production induced by
Cl-IB-MECA was much larger than that induced by CCPA (Fig. 2B
). Thus, the A1 and
A3 receptors appeared selectively coupled to PLC
and PLD, respectively.
|
The cardioprotective effects of adenosine A1 and
A3 receptors are mediated by PLC and PLD, respectively
The next objective was to investigate whether activation of PLC
and of PLD mediates the cardioprotective effects induced by
A1 and A3 receptors,
respectively. The data showed that this is in fact the case. First, the
PLC-selective inhibitor U-73122 blocked most of the CCPA-induced
accumulation of DAG (Fig. 3A
). In parallel, U-73122 was also able to abolish the
A1 agonist-induced activation of PLC (not shown).
On the other hand, U-73122 exerted only moderate inhibitory effects on
the accumulation of DAG (Fig. 3A
) and activation of PLD (not
shown) induced by Cl-IB-MECA. Second, U-73122 abolished the
cardioprotective effect of CCPA but had no effect on that of Cl-IB-MECA
(Fig. 3B
). These data are thus consistent with the
hypothesis that PLC mediates the cardioprotective effect of the
A1 receptor but does not play a role in
A3 receptor-induced protection.
|
The role of PLD in the cardioprotective effects of adenosine
A1 and A3 receptor agonists
was similarly investigated by selective inhibition of DAG formation by
this enzyme. Ethanol or butanol inhibits the formation of phosphatidic
acid (and therefore that of DAG) mediated by PLD as a result of
PLD-catalyzed transphosphatidylation of the alcohol (14
15
16
, 18)
. Ethanol inhibited the A3
agonist-induced accumulation of DAG (Fig. 3C
) and abolished
A3 agonist-induced cardioprotection (Fig. 3D
). In contrast, neither the DAG accumulation (Fig. 3C
) nor the cardioprotective response (Fig. 3D
)
induced by the A1 receptor was affected by
ethanol. Similar data were obtained with butanol in place of ethanol
(not shown).
Additional evidence that PLD selectively mediates the cardioprotective
effect of the A3 receptor was provided by the
observation that propranolol, which inhibits the conversion of
phosphatidic acid to DAG (15
, 18)
, blocked the
A3 agonist-induced accumulation of DAG (Fig. 3C
) as well as the cardioprotection afforded by this agonist
(Fig. 3D
). In contrast, propranolol had virtually no effect
on DAG accumulation (Fig. 3C
) or cardioprotection (Fig. 3D
) induced by CCPA. Thus, the adenosine
A3 receptor signals selectively through PLD to
induce its cardioprotective effect, whereas the
A1 receptor acts via PLC to achieve
cardioprotection.
The A3 receptor is likely present on the cardiac cell and not on nonmyocytes such as the fibroblast for the following reasons. First, the A3 receptor agonist Cl-IB-MECA is able to inhibit the isoproterenol-stimulated increase in the contractility of these chick cardiac myocyte (data not shown). Since fibroblasts are not excitable cells and do not contract, the A3 agonist effect on contractility is likely due to myocyte A3 receptor activation. Second, it is unlikely that adenosine receptors of fibroblasts play an important role in cardioprotection because the principal nonmyocytes in these cultures, the fibroblasts, express predominantly the A2B receptor, and because the A3 agonist Cl-IB-MECA at the concentrations used does not cause significant stimulation of the A2B receptor.
PLD mediates the cardioprotective effect induced by activation of
human adenosine A3 receptors expressed in chick atrial
myocytes
Atrial myocytes cultured from embryonic chick hearts lack native
A3 receptors (9)
. The
cardioprotection induced by a brief period of ischemia in these cells
is thus of shorter duration than that apparent with ventricular
myocytes (Fig. 4A
) and is characteristic of an A1
receptor response (9)
. Transfection of chick atrial
myocytes with a vector encoding the human adenosine
A3 receptor confers a sustained cardioprotective
response to A3 agonists (9)
. The
acquisition of this sustained cardioprotective response is associated
with the appearance of A3 agonist-induced
increases in both DAG abundance and PLD activity (Fig. 4B
).
The A3 agonist-induced accumulation of DAG was
abolished by ethanol but was unaffected by U-73122 (Fig. 4C
), suggesting that the human adenosine
A3 receptor selectively couples to PLD when
expressed in chick atrial myocytes. The cardioprotection mediated by
the human adenosine A3 receptor was also
abolished by ethanol or propranolol (Fig. 4D
) but was not
affected by U-73122 (data not shown). These data show that the human
A3 receptor signals selectively through PLD to
achieve its cardioprotective effect.
|
Additive cardioprotective effects of adenosine A1 and
A3 receptor agonists
The specificity of the A1 receptor–PLC and
A3 receptor–PLD linkages and the consequent
distinct biological effects mediated by each receptor suggested that
concomitant activation of both receptors may result in a response
greater than that triggered by the activation of either receptor alone.
Indeed, the extent of cardioprotection induced by the combination of
A1 and A3 receptor agonists
was greater than that apparent with an equivalent concentration of
either agonist alone (Fig. 5
). These data indicate a productive, additive interaction between the
two adenosine receptors that elicits a potent cardioprotective response
in the cardiac myocyte.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3
4
5
, 11
, 23)
. Although
activation of adenosine receptors has been shown to mediate these
cardioprotective effects of adenosine, the cellular and molecular
mechanisms downstream of the receptor remain incompletely understood.
Both the A1 and A3
adenosine receptors can trigger and mediate the cardioprotective effect
of ischemic preconditioning. However, the preconditioning effect
mediated by the A3 receptor is more sustained
than that induced by activation of the A1
receptor (9)
. The objective of the current study was to
investigate the signaling mechanism that acts downstream of
A1 or A3 receptors in
mediating these distinct preconditioning effects. Although PLD has been
implicated in ischemic preconditioning (25)
, the coupling
of PLD to a specific adenosine receptor and its role in mediating the
preconditioning effect induced by adenosine are unknown. A previously
established cardiac myocyte model of ischemic preconditioning (5
, 9
, 10)
was used to test the hypothesis that the distinct
cardioprotective effects of adenosine are mediated by differential
coupling of A1 and A3
receptors to PLC and PLD, respectively. Multiple lines of evidence are
provided to support this hypothesis.
First, activation of the adenosine A3 receptor
causes a more pronounced and sustained stimulation of the DAG
accumulation than does the activation of A1
receptors, consistent with a selective coupling of the
A3 receptor to stimulation of PLD. This coupling
was determined directly by showing that activation of the
A3 receptor causes a much more pronounced
stimulation of the PLD activity than does the A1
receptor. The coupling of the adenosine A3
receptor to PLD activation has also been observed in a rat mast cell
line (26)
. In contrast, the A1
receptor mediates a greater increase in the PLC activity than does the
A3 receptor. Thus, the A1
receptor is selectively coupled to PLC, whereas the
A3 receptor is coupled to PLD. Second, activation
of PLC is responsible for the A1
receptor-mediated cardioprotective effect. The PLC inhibitor U-73122
blocked the A1 agonist-induced activation of PLC,
accumulation of DAG, and cardioprotective effect. In contrast, U-73122
had no effect on the cardioprotective effect mediated by the
A3 receptor. Although the selectivity of U-73122
for PLC vs. PLD is unclear, U-73122 could abolish the PLC activation.
The present data show that U-73122 clearly has a different effect on
the A1 receptor–PLC linkage than it does on the
A3 receptor–PLD linkage. The data obtained with
U-73122 support the hypothesis that PLC mediates the cardioprotective
response to A1 receptor agonist, but not to the
A3 receptor agonist.
In establishing the third line of evidence, the role of PLD was also determined by selective inhibition of DAG formation by this enzyme. Ethanol or butanol can inhibit the formation of DAG mediated by PLD because of PLD-catalyzed transphosphatidylation of the alcohol. Ethanol or butanol inhibited the A3 agonist-stimulated accumulation of DAG and cardioprotective effect. In contrast, the alcohol had no effect on the A1 agonist-stimulated DAG accumulation or cardioprotective response. Additional evidence for this concept was obtained by the finding that propranolol, which inhibits the conversion of phosphatidic acid to DAG, blocked the A3 agonist-induced DAG accumulation and cardioprotective response. On the other hand, propranolol had no effect on the A1 agonist-induced DAG accumulation or cardioprotective response. Although propranolol is also a ß-adrenergic blocker, there was no exogenous or endogenous catecholamine during the experimental conditions. Most likely, the effect of propranolol on A1 and A3 receptor-mediated cardioprotection is due to its selective inhibitory effect on the A3 receptor-PLD coupling.
Finally, atrial cardiac myocytes cultured from embryonic chick hearts,
which lack native A3 receptor, were used to
determine the specificity of adenosine A3
receptor–PLD coupling. The role of PLD in coupling to human adenosine
A3 receptor and in mediating the cardioprotective
effect induced by the human adenosine A3 receptor
was investigated. Previous study showed that these myocytes can be
efficiently transfected and that transfection of atrial myocytes with
human A3 receptor cDNA conferred a sustained
cardioprotective response to A3 agonist
(9)
. The current study shows that transfection with human
adenosine A3 receptor cDNA results in the
appearance of an A3 agonist-induced increase in
both DAG level and PLD activity. Ethanol blocked the DAG accumulation
and the cardioprotective effect mediated by the human adenosine
A3 receptor. In contrast, the PLC inhibitor
U-73122 had no effect on the DAG accumulation or the cardioprotective
effect induced by activation of the human A3
receptor. Thus, the human adenosine A3 receptor
is selectively coupled to PLD in achieving its cardioprotective effect.
In conclusion, the present data show that the distinct cardioprotective effects of adenosine acting at the A1 and A3 subtypes of adenosine receptors are mediated by selective coupling of these receptors to phospholipases C and D, respectively. The different signaling mechanisms that underlie the distinct A1 and A3 receptor-mediated protective responses raised the possibility that the two receptor pathways may interact in a productive manner to elicit an additive cardioprotective effect. The present data indicate that this is indeed the case. The concomitant presence of both A1 and A3 receptor agonists induced a greater cardioprotective effect than that produced by an equivalent concentration of either agonist alone. The present findings are important for our understanding of the basic biology of cardioprotection, an important self-adaptive mechanism intrinsic to the heart. Highly relevant to this investigative effort, our data indicate that agonists capable of activating both A1 and A3 receptors are thus likely to provide protection from ischemia at lower doses than those required for selective agonists and therefore should have fewer potentially adverse side effects. Agonists that act at both A1 and A3 adenosine receptors may prove therapeutically beneficial in the treatment of ischemic heart disease.
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ACKNOWLEDGMENTS |
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Received for publication August 18, 1999.
Revision received December 10, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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