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1 Department of Pathology, Duke University Medical Center, Durham 27710; 2 National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and 3 Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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To determine whether A3 adenosine receptor (A3AR) signaling modulates myocardial function, energetics, and cardioprotection, hearts from wild-type and A3AR-overexpressor mice were subjected to 20-min ischemia and 40-min reperfusion while 31P NMR spectra were acquired. Basal heart rate and left ventricular developed pressure (LVDP) were lower in A3AR-overexpressor hearts than wild-type hearts. Ischemic ATP depletion was delayed and postischemic recoveries of contractile function, ATP, and phosphocreatine were greater in A3AR-hearts. To determine the role of depressed heart rate and to confirm A3AR-specific signaling, hearts were paced at 480 beats/min with or without 60 nmol/l MRS-1220 (A3AR-specific inhibitor) and then subjected to ischemia-reperfusion. LVDP was similar in paced A3AR-overexpressor and paced wild-type hearts. Differences in ischemic ATP depletion and postischemic contractile and energetic dysfunction remained in paced A3AR-overexpressor hearts versus paced wild-type hearts but were abolished by MRS-1220. In summary, A3AR overexpression decreased basal heart rate and contractility, preserved ischemic ATP, and decreased postischemic dysfunction. Pacing abolished the decreased contractility but not the ATP preservation or cardioprotection. Therefore, A3AR overexpression results in cardioprotection via a specific A3AR effect, possibly involving preservation of ATP during ischemia.
cardioprotection; ischemia; nuclear magnetic resonance spectroscopy
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ADENOSINE IS an endogenous metabolite that is released from the myocardium during ischemia-reperfusion. Exogenous administration of adenosine or adenosine receptor agonists has been shown to be cardioprotective (20, 26). Because of its potent cardioprotective effects, much attention has focused on the use of adenosine as a cardiotherapy. Thus far the main approach in therapy development has been to administer adenosine, adenosine receptor agonists, or modulators of adenosine degradation (15, 22). Clinical use of such approaches is complicated by the effects of these agents on noncardiac tissue and by progressive desensitization of adenosine receptors. Cardiac-specific targeting could alleviate some of these problems. Therefore, a transgenic mouse model was recently developed with cardiac-specific overexpression of the Gi/o-coupled A1 adenosine receptor (A1AR) (23). Hearts from these mice were inherently resistant to ischemia, indicating that increasing the number of functional adenosine receptors alone can enhance endogenous adenosine signaling and lead to cardioprotection.
Although it is thought that the cardioprotective effects of adenosine
are mediated primarily via the A1AR, recent evidence suggests that signaling through the A3 adenosine receptor
(A3AR), which also couples to Gi/o, could be
protective (1, 28, 31). Although levels of the
A3AR are low in cardiac tissue from most species (29,
32), A3AR overexpression could be useful as a genetic therapy. To determine whether cardiac-specific overexpression of the A3AR protects against ischemic injury,
transgenic mice were created with a gene construct consisting of the
canine A3AR cDNA under the control of the 
-myosin heavy
chain promoter (2). It was demonstrated that, after in
vivo regional ischemia and reperfusion, infarct size was lower
in low copy number A3AR overexpressors than in wild-type
mice, confirming that A3AR signaling could protect against
myocardial necrosis (2). In the present study, we
determined whether cardiac-specific overexpression of the
A3AR could also protect against postischemic
contractile dysfunction after short periods of ischemia.
Perfused hearts from A3AR-overexpressor and wild-type mice
were subjected to 15- or 20-min global ischemia and 40-min
reperfusion. Because adenosine has negative chronotropic effects
(14) and cardioprotection has been related to preservation of ischemic ATP (8, 24, 27) and intracellular pH
levels (5, 7, 19), contractile parameters and energetics
were also studied in the A3AR-overexpressor hearts.
Furthermore, the canine A3AR-specific inhibitor, MRS-1220,
was used to confirm that any observations in the
A3AR-overexpressor hearts were indeed due to
A3AR signaling.
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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
Transgenic mice exhibiting cardiac-specific overexpression of the A3AR were created by microinjection of a transgene construct, containing canine A3AR cDNA under the control of the-myosin heavy chain promoter, into the pronuclei of fertilized
FVB/N mouse oocytes (2). After embryo implantation, the
presence of the transgene in the resultant founder mice was confirmed
by Southern blot analysis and expression of canine A3AR
mRNA was determined by Northern blot analysis. A3AR levels
were assessed in the transgenic lines by radioligand binding assays
(2).
In the present study, 15 heterozygous low copy number transgenic mice (A3tg.1) and 16 of their wild-type littermates were used; all animals were treated in accordance with National Institutes of Health (NIH) guidelines and the "Guiding Principles for Research Involving Animals and Human Beings" of the American Physiological Society. Binding assays revealed 12.7 fmol/mg of G protein-coupled A3ARs in A3tg.1 hearts and negligible levels in wild-type littermates. A3tg.1 hearts exhibited no evidence of cardiac abnormalities, as determined from morphological and histochemical analysis and determination of expression of hypertrophic marker genes (2).
Ischemia-Reperfusion Protocol
Hearts were isolated and perfused in the Langendorff mode as described previously (4). Hearts were then subjected to 20 min of no-flow ischemia followed by 40-min reperfusion. Left ventricular developed pressure (LVDP), rate of contraction (+dP/dt), rate of relaxation (
dP/dt), and heart
rate were monitored via a water-filled latex balloon in the left
ventricle. Recovery of contractile function was assessed by measurement
of LVDP at the end of reperfusion and expressed as a percentage of
preischemic LVDP.
Control Hearts, Pacing Protocol, and MRS-1220 Treatment
A control group of untreated A3tg.1 (n = 5) and wild-type (n = 6) hearts was allowed to beat at their intrinsic heart rate, and another group of A3tg.1 (n = 5) and wild-type (n = 5) hearts was paced throughout preischemia, and reperfusion at 8 Hz with a 4-ms square pulse generated by a Grass stimulator (Grass-Telefactor). We found that pacing itself increased ischemic injury (unpublished observations); therefore, the ischemic period was reduced to 15 min in the paced hearts to provide a suitable level of postischemic recovery of contractile function. A further group of A3tg.1 (n = 5) and wild-type (n = 5) hearts was paced at 8 Hz and then treated with 60 nmol/l of the canine A3AR-specific inhibitor MRS-1220, beginning 5 min before the 15-min ischemic period and continuing throughout reperfusion.NMR Spectroscopy
Relative changes in concentrations of phosphorus metabolites were observed during the ischemia-reperfusion protocols by acquiring consecutive 31P NMR spectra as described previously (6). The areas of the spectral peaks were expressed as a percentage of the peak areas of an initial, preischemic control spectrum from each heart. Intracellular pH was estimated from the chemical shift of the Pi peak relative to phosphocreatine (PCr) with previously obtained titration curves.Statistics
Results are expressed as means ± SE. Significance (P
0.05) was determined for discrete variables by
one-way analysis of variance and for continuous variables by analysis
of variance for repeated measures; both analyses were followed by a
Fisher's post hoc test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Basal Contractile Function
During the preischemic period, LVDP was lower in unpaced A3AR-overexpressor hearts (87 cmH2O) than in unpaced wild-type hearts (110 cmH2O) (P < 0.0001; Table 1). Heart rate was also lower 319 beats/minute in unpaced A3AR-overexpressor hearts than in unpaced wild-type hearts (390 beats/min). +dP/dt (2.8 cmH2O/ms in A3AR overexpressors vs. 3.9 cmH2O/ms in wild type) anddP/dt (2.1 cmH2O/ms in
A3AR overexpressors vs. 3.0 cmH2O/ms in wild type) (P < 0.001; Table 1) were also lower in unpaced
A3AR-overexpressor hearts than in unpaced wild-type hearts.
Thus basal myocardial contractility was decreased by overexpression of
the A3AR.
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On pacing at 480 beats/min, LVDP increased in
A3AR-overexpressor hearts to 109 cmH2O
(P < 0.0001 vs. unpaced A3AR
overexpressors), whereas LVDP did not differ in paced versus unpaced
wild-type hearts (Table 1). +dP/dt and dP/dt
were also increased by pacing in A3AR-overexpressor hearts,
to 3.8 cmH2O/ms and 2.8 cmH2O/ms, respectively. The increase in LVDP, +dP/dt, and
dP/dt in paced A3AR-overexpressor hearts
resulted in these values not being significantly different from those
of paced or unpaced wild-type hearts (Table 1).
Pretreatment of paced hearts with 60 nmol/l of the
A3AR-specific inhibitor MRS-1220 had no effect on LVDP,
+dP/dt, or dP/dt in either A3AR-overexpressor
or wild-type hearts (Table 1).
Postischemic Contractile Recovery
Recovery of contractile function after 20-min ischemia and 40-min reperfusion was higher in unpaced A3AR-overexpressor hearts (56% initial LVDP) than in unpaced wild-type hearts (30% initial LVDP) (P < 0.0001; Fig. 1). Postischemic contractile function was also higher in absolute terms in unpaced A3AR hearts (49 ± 2 cmH2O) than in unpaced wild-type hearts (33 ± 4 cmH2O) (P < 0.05).
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In paced hearts, recovery of contractile function after 15-min ischemia and 40-min reperfusion was also higher in A3AR overexpressors (60% initial LVDP) than in wild type (35% initial LVDP) (P < 0.001; Fig. 1). Postischemic contractile function was also higher in absolute terms in paced A3AR hearts (65 ± 4 cmH2O) than in paced wild-type hearts (39 ± 6 cmH2O) (P < 0.001).
Pretreatment with 60 nmol/l MRS-1220 lowered functional recovery after 15-min ischemia and 40-min reperfusion in paced A3AR-overexpressor hearts to 27% initial LVDP (P < 0.0001 vs. untreated paced A3AR overexpressors), which was not significantly different from that observed in untreated paced wild-type hearts (35% initial LVDP) or MRS-1220-treated paced wild-type hearts (28% initial LVDP) (Fig. 1). Postischemic LVDP was also lower, at 40 ± 6 cmH2O, in MRS-1220-treated versus untreated paced A3AR-overexpressor hearts (P < 0.0001). Pretreatment with MRS 1220 had no significant effect on percent recovery of contractile function (28% initial LVDP) or absolute LVDP (29 ± 6 cmH2O) in paced wild-type hearts.
Phosphate Metabolites and Intracellular pH
Phosphate metabolites and intracellular pH were measured in the transgenic and wild-type hearts to determine whether overexpression of the A3AR altered myocardial energetics and pH regulation.ATP levels.
During ischemia, ATP depletion was delayed in the unpaced
A3AR-overexpressor hearts compared with wild-type hearts
(Fig. 2A), but by the end of
20-min ischemia, ATP levels were the same in unpaced
A3AR-overexpressor and wild-type hearts, both at ~20% initial ATP. By the end of reperfusion, ATP had increased to a greater
extent in unpaced A3AR-overexpressor hearts, which reached 50% initial ATP, than in unpaced wild-type hearts, which reached 24%
initial ATP (P < 0.01; Fig. 2A).
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3.6 ± 0.8% initial ATP/min in unpaced A3AR-overexpressor hearts
to 5.4 ± 0.4% initial ATP/min in paced
A3AR-overexpressor hearts (P < 0.05) and
from 5.1 ± 0.2% initial ATP/min in unpaced wild-type hearts to
7.1 ± 0.4% initial ATP/min in paced wild-type hearts
(P < 0.05). Confirming the delay in ATP depletion in
A3AR-overexpressor versus wild-type hearts, the rate of ATP
depletion was significantly lower in both unpaced
A3AR-overexpressor versus unpaced wild-type hearts
(P < 0.05) and paced A3AR-overexpressor
versus paced wild-type hearts (P < 0.05).
PCr levels. During ischemia, PCr levels fell in all hearts. At the end of ischemia, there were no differences in PCr levels (~5% initial PCr) between unpaced A3AR-overexpressor and wild-type hearts (Fig. 2B) or between any of the paced groups, all also at ~5% of initial PCr (Fig. 3B). Although PCr levels were not different during early reperfusion, by the end of reperfusion PCr levels had increased to a greater extent in unpaced A3AR-overexpressor hearts, which reached 66% of initial PCr, than in unpaced wild-type hearts, which reached 42% of initial PCr (P < 0.05; Fig. 2B).
In paced hearts, reperfusion PCr levels recovered to a greater extent in A3AR-overexpressor hearts, which reached 107% of initial PCr by the end of reperfusion, than in wild-type hearts, which reached 74% of initial PCr (P < 0.001; Fig. 3B). Pretreatment with MRS-1220 abolished the increased PCr recovery during reperfusion in paced A3AR-overexpressor hearts, end-reperfusion PCr levels being 67% of initial PCr in MRS-1220-treated paced A3AR-overexpressor hearts (P < 0.001 vs. untreated paced A3AR overexpressors), which was not significantly different from that observed in untreated paced wild-type hearts (74% initial PCr) or MRS-1220-treated paced wild-type hearts (62% initial PCr). Pretreatment with MRS-1220 had no significant effect on reperfusion ATP levels in paced wild-type hearts.Intracellular pH. During ischemia, pH decreased in all hearts. At the end of ischemia, there were no differences in pH levels, at pH ~5.80, between unpaced A3AR-overexpressor and wild-type hearts (Fig. 2C) or between any of the paced groups, all also at pH ~5.80 (Fig. 3C). During reperfusion, pH increased in all hearts back to preischemic values. At the end of reperfusion, there were also no differences in pH levels, at pH ~7.10, between unpaced A3AR-overexpressor and wild-type hearts (Fig. 2C) or between any of the paced groups, all at pH ~7.10 (Fig. 3C).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of A3AR Overexpression on Heart Rate, Basal Contractility, Energetics, and Postischemic Dysfunction
In the present study, preischemic heart rate, peak contraction (LVDP), +dP/dt, anddP/dt were
lower in perfused hearts from A3AR-overexpressor mice than
wild-type mice (Table 1). This observation of A3AR-induced
negative chronotropy and inotropy is reminiscent of that induced by
exogenous adenosine or by overexpression of the A1AR
(14, 23). The A3AR-overexpressor and wild-type
hearts were then subjected to 20-min ischemia and 40-min
reperfusion. During ischemia, the decrease in PCr and
intracellular pH were similar in A3AR-overexpressor and
wild-type hearts (Fig. 2). However, ischemic ATP depletion was
delayed in the A3AR-overexpressor hearts compared with
wild-type hearts, the rate of fall of ATP being 3.6% initial ATP/min
in A3AR-overexpressor hearts compared with 5.1% initial
ATP/min in wild-type hearts during the first 15 min of
ischemia. During reperfusion, recovery of the energy
metabolites ATP and PCr was faster in A3AR-overexpressor
hearts than wild-type hearts (Fig. 2). In addition,
postischemic contractile dysfunction was lower in
A3AR-overexpressor hearts than wild-type hearts (Fig. 1).
It appears, therefore, that overexpression of the A3AR
results in short-term preservation of ATP levels during
ischemia and protects against postischemic contractile
and energetic dysfunction.
Effect of Pacing on Contractility, Energetics, and Postischemic Dysfunction in A3AR-Overexpressor Versus Wild-Type Hearts
Depressed preischemic heart rate and contractility can lead to decreased ATP utilization and increased postischemic recovery (17). To determine whether depressed heart rate was responsible for the ischemic ATP preservation and cardioprotection in the A3AR overexpressors, hearts were paced at 480 beats/min throughout the protocol. Pacing increased LVDP, +dP/dt, anddP/dt in
A3AR-overexpressor hearts but, surprisingly, had no effect
on these parameters in wild-type hearts (Table 1). Although surprising,
this finding is consistent with recent studies indicating that the
force-frequency response is biphasic in mouse hearts. It has been shown
that increasing heart rate in the range of 300-400 beats/min
results in increased developed pressure, whereas increasing heart rate
from 400 beats/min upward either has no effect or decreases developed
pressure (9, 16). The peak of the force-frequency curve in
mice varies slightly with different experimental models (9,
16). Our results would suggest a positive force-frequency
relationship in the 300- to 400 beats/min range and a plateau in the
400- to 500 beats/min range in isolated mouse hearts, consistent with a
recent study by Headrick et al. (13).
Pacing itself increased the rate of ischemic ATP depletion from
3.6 to 5.4% initial ATP/min in A3AR-overexpressor
hearts and from 5.1 to 7.1% initial ATP/min in wild-type hearts
over the 15-min ischemic period. As can be seen from these
values, despite the equivalent contractility in paced
A3AR-overexpressor hearts compared with paced wild-type
hearts, ATP depletion remained slower in the
A3AR-overexpressor hearts at 5.4% initial ATP/min in
paced A3AR-overexpressor hearts compared with 7.1%
initial ATP/min in paced wild-type hearts. Likewise, the
postischemic recovery of ATP, PCr, and contractile function
remained greater in the paced A3AR-overexpressor hearts
compared with paced wild-type hearts (Figs. 1 and 3). From these
results, we can conclude that the preservation of ischemic ATP
and the reduced postischemic contractile and energetic
dysfunction in the A3AR-overexpressor hearts were not due
to the decreased basal heart rate and contractility induced by
A3AR overexpression.
Effect of A3AR Inhibition on Contractility, Energetics, and Postischemic Dysfunction in A3AR-Overexpressor Versus Wild-Type Hearts
To determine whether the ischemic ATP preservation and cardioprotection observed in A3AR-overexpressor hearts was due specifically to A3AR signaling, and not to secondary alterations induced by the presence of the transgene, paced hearts were pretreated with 60 nmol/l of a canine A3AR-specific inhibitor, MRS-1220. The concentration of MRS-1220 was chosen on the basis of the MRS-1220 inhibitor constant for the canine A3AR of 6 nmol/l (18) and on preliminary dose-response studies in isolated hearts. The 60 nmol/l concentration had no effect on contractile function; LVDP, +dP/dt, anddP/dt being the same before and after infusion of 60 nmol/l MRS-1220 in both paced wild-type and paced
A3AR-overexpressor hearts (Table 1).
Pretreatment with MRS-1220 completely abolished the ischemic ATP preservation and the greater postischemic recovery of ATP, PCr, and contractile function in the A3AR-overexpressor compared with wild-type hearts (Figs. 1 and 3). It appears, therefore, that the preservation of ischemic ATP levels and the protection from postischemic contractile and energetic dysfunction observed in the A3AR-overexpressor hearts were mediated specifically by the A3AR and were not due to adaptive alterations induced by long-term A3AR overexpression.
In summary, we have demonstrated that cardiac-specific overexpression of the A3AR results in decreased basal heart rate and contractility, short-term ischemic ATP preservation, and protection from postischemic contractile and energetic dysfunction. Depressed preischemic contractility can itself be protective. However, by pacing hearts at a rate that resulted in similar contractile function in the A3AR-overexpressor hearts as in wild-type hearts, we demonstrated that the depressed contractility had no role in the ischemic ATP preservation and cardioprotection in the A3AR-overexpressor hearts. By pretreating hearts with the A3AR-specific inhibitor MRS-1220, we also demonstrated that the energetic and functional effects observed in the A3AR-overexpressor hearts were mediated specifically by the A3AR. Together, these results imply that myocardial A3AR signaling is cardioprotective and leads to preservation of ischemic ATP levels. Because cardioprotection was coincident with decreased ATP depletion in all our experiments, the decreased ATP depletion may be the mechanism by which A3AR signaling leads to cardioprotection. Interestingly, decreased ATP depletion during ischemia was also found to be coincident with protection in A1AR-overexpressor hearts (12), suggesting that the A3AR and A1AR may mediate protection via a common mechanism of energy preservation.
To our knowledge, this is the first study to assess the energetic consequences of cardiac-specific overexpression of the A3AR and is also the first study to determine the effects of A3AR overexpression on postischemic contractile dysfunction after short-term ischemia. Our results support the use of cardiac-specific expression techniques. Previous studies showed that, although A3AR agonists can have direct beneficial effects on isolated hearts (11), A3AR signaling in mast cells may be detrimental to the myocardium via proinflammatory mechanisms (21, 25, 30), such that systemic A3AR inhibition can actually be protective (3, 10). These studies highlight the necessity for cardiac-specific A3AR targeting in future therapeutic approaches and also highlight the possible complications of using systemic A3AR agonists as cardioprotective agents.
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ACKNOWLEDGEMENTS |
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The authors thank Robert E. London for use of the NMR facilities and Scott A. Gabel for assistance with the pacing apparatus.
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FOOTNOTES |
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This work was supported by National Institutes of Health grants (to C. Steenbergen and J. Auchampach).
Address for reprint requests and other correspondence: H. R. Cross, Dept. of Pathology, Box 3712, Duke Univ. Medical Center, Durham NC 27710 (E-mail: cross017{at}mc.duke.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.
June 20, 2002;10.1152/ajpheart.00335.2002
Received 25 February 2002; accepted in final form 17 June 2002.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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