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Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We have previously shown that ischemic preconditioning (IP) improves cardiac performance and sarcoplasmic reticulum (SR) function in hearts subjected to ischemia-reperfusion (I/R). In this study, we examined the effect of IP on I/R-induced changes in gene expression for SR proteins such as the Ca2+ release channel, Ca2+ pump ATPase, phospholamban, and calsequestrin in the isolated rat heart. Normal isolated rat hearts exposed to three brief cycles of IP (5-min ischemia and 5-min reperfusion) exhibited a significant decrease in the transcript levels of SR genes. Nonpreconditioned I/R hearts when subjected to 30-min ischemia and 30-min reperfusion showed a marked decrease in mRNA levels for the SR proteins compared with normal hearts; this decrease was attenuated by preconditioning. Although hearts subjected to Ca2+ paradox (CP) have been shown to exhibit intracellular Ca2+ overload and SR dysfunction like those in I/R hearts, virtually nothing is known regarding the effect of CP on cardiac SR gene expression. Accordingly, CP (5-min Ca2+-free perfusion and 30-min reperfusion with normal medium) was observed to produce dramatic changes in SR gene expression, and the heart failed to contract; these alterations were attenuated by IP. Our results show that 1) both I/R and CP depress SR gene expression in the normal heart, 2) IP attenuates I/R- and CP-induced depression in cardiac function and SR gene expression, and 3) intracellular Ca2+ overload may play a role in depressing SR gene expression in both I/R and CP hearts.
ischemic preconditioning; ischemia-reperfusion; cardiac mRNA levels; Ca2+ paradoxic heart
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ISCHEMIC PRECONDITIONING (IP) was first defined by Murry et al. (14) as repetitive cycles of brief ischemia and reperfusion that protected the heart against a subsequent period of prolonged ischemic injury. IP has been shown to enhance the recovery of cardiac function (4, 16), decrease the incidence of arrhythmias (8, 19), and reduce infarct size (8) in hearts subjected to ischemia-reperfusion (I/R) injury. Several endogenous mediators such as adenosine, norepinephrine, protein kinase C, and free radicals have been proposed to mediate the beneficial effects of IP (11). Earlier, we (9) reported that IP improved cardiac performance not only in hearts exposed to I/R (16) but also in hearts subjected to Ca2+ paradox (CP). CP is known to occur as a consequence of a brief period of Ca2+ depletion followed by Ca2+ repletion (28) and is considered to be an appropriate model for studying the effect of intracellular Ca2+ overload as a contributing factor in the pathogenesis of cardiac dysfunction (1, 2).
By virtue of its ability to regulate the intracellular concentration of free Ca2+, the sarcoplasmic reticulum (SR) plays a central role in the cardiac contraction-relaxation cycle. We (25, 26) reported that I/R depressed mRNA levels for the SR Ca2+-cycling proteins such as the ryanodine receptor (RyR) or Ca2+ release channel, Ca2+ pump ATPase [sarco(endo)plasmic Ca2+-ATPase (SERCA2a)], phospholamban (PLB), and calsequestrin (CQS). In view of the protective effect of IP at the level of SR function in I/R and CP hearts (9, 16), this study was designed to examine the effect of IP in preventing changes in SR gene expression due to I/R and CP.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Heart perfusion and experimental protocol.
Male Sprague-Dawley rats weighing 250-300 g were anesthetized with
a mixture of ketamine (60 mg/kg) and xylazine (10 mg/kg). The hearts
were rapidly excised, cannulated to the Langendorff apparatus, and
perfused with Krebs-Henseleit solution gassed with a mixture of 95%
O2 and 5% CO2; pH 7.4. The perfusion medium
contained (in mmol/l) 120 NaCl, 25 NaHCO3, 11 glucose, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4, and
1.25 CaCl2. The hearts were electrically stimulated at a
rate of 300 beats/min (Phipps and Bird; Richmond, VA), and the
perfusion rate was maintained at 10 ml/min. A water-filled latex
balloon was inserted in the left ventricle and connected to a pressure
transducer for the left ventricular systolic and diastolic pressure
measurements. The left ventricular developed pressure (LVDP) and the
left ventricular end-diastolic pressure (LVEDP) were measured using the
Acknowledge 3.5.3 software for Windows (BIOPAC Systems; Goleta, CA).
LVDP was the difference between left ventricular systolic pressure and
LVEDP. All hearts were stabilized for a period of 30 min before use and
were randomly distributed into the different experimental groups (Fig.
1). In one series of experiments, control
hearts were perfused for 30 or 60 min after stabilization, and because
no significant differences were observed in the level of SR gene
expression, the control values were grouped together. The I/R hearts
were made globally ischemic by stopping the coronary flow
for 30 min, after which the flow was restored for 30 min. For the
preconditioning group, one set of hearts was collected after three
cycles of 5-min ischemia and 5-min reperfusion (IP), and the
second set was collected by subjecting IP hearts to the I/R protocol
(IP+I/R). Another series of experiments was conducted to test the
effects of IP on CP-induced changes in SR gene expression. For this
purpose, control hearts were perfused for 53 min after stabilization,
whereas the CP hearts were perfused with normal medium for 18 min
followed by 5 min of Ca2+-free perfusion and 30 min of
perfusion with normal medium containing 1.25 mM Ca2+. For
the preconditioning group, one set of hearts was collected after three
cycles of 3-min ischemia and 3-min reperfusion, and the other
set was collected after the CP protocol (IP+CP). The perfusion
procedures (Fig. 1) were similar to those in our previous reports
(9, 16). The experimental protocol in the present investigation was approved by the Animal Care Committee of the University of Manitoba and conformed with the Canadian Council on
Animal Care concerning the "Care and Use of Experimental Animals" (Vol. 1, 2nd Ed., 1993).
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RNA isolation and Northern blot analysis.
Total RNA was extracted from the ventricular tissue by the guanidinium
thiocyanate method described previously (25). Samples normalized to 5, 10, 20, 30, and 40 µg total RNA were denatured with
formaldehyde and electrophoresed in a 1.2% agarose-formaldehyde gel.
The linearity of the procedure used for the quantification of RyR,
SERCA2a, PLB, and CQS is shown in Fig. 2,
A-D. Twenty micrograms total RNA were used in the rest
of the study because it is in the linear range. The Random Primer DNA
Labeling System and T4 Polynucleotide Kinase kits (GIBCO-BRL Life
Technologies; Gaithersburg, MD) were used to label the cDNAs and
oligonucleotides, respectively. Inserts were separated from recombinant
plasmids and used as probes (25). 18S mRNA was used as an
internal standard.
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Statistical analysis. Results are expressed as means ± SE. Statistical analyses were performed using ANOVA followed by Student's unpaired t-test for multiple comparisons. A linear regression test was used for the linearity study. Values of P < 0.05 were considered to be statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Table 1 shows that I/R and CP
depressed LVDP by 75% and 94% and increased LVEDP by 13- and 8.6-fold
in nonpreconditioned hearts, respectively. IP improved LVDP by 71.5%
in the I/R hearts and by 26.8% in the CP hearts, whereas LVEDP was
higher than the control level by 4.6-fold in the I/R hearts and 5-fold
in the CP hearts. At the level of SR gene expression, three cycles of IP (5-min ischemia and 5-min reperfusion) decreased
(P < 0.05) the mRNA levels of RyR (by 33%), SERCA2a
(by 21%), and PLB (by 23%) but had no effect on the mRNA levels of
CQS (Fig. 3, A-E). Compared with the control group, I/R (30-min ischemia and
30-min reperfusion) decreased the mRNA levels for RyR, SERCA2a, PLB, and CQS by 60%, 34%, 50%, and 46% in the nonpreconditioned hearts, respectively. The alterations in SR gene expression were significantly protected by 70% for RyR, 84% for SERCA2a, 62% for PLB, and 71% for
CQS when I/R hearts were preconditioned. Some 30-min ischemic hearts were reperfused for 60 min, but the results with respect to
changes in SR gene expression were similar to those observed in
ischemic hearts reperfused for 30 min. Results similar to these were obtained when the I/R hearts were preconditioned with three cycles
of 3-min ischemia and 3-min reperfusion (data not shown, n = 2).
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In the CP experiments, three cycles of IP (3-min ischemia
and 3-min reperfusion) significantly decreased the expression of RyR
(by 29%), SERCA2a (by 27%), and PLB (by 15%) but not that of CQS
(Fig. 4, A-E). Hearts
subjected to CP (5-min Ca2+-free perfusion and 30-min
reperfusion) showed a marked depression in mRNA levels of RyR (by
62%), SERCA2a (by 89%), PLB (by 59%), and CQS (by 76%) compared
with control hearts. IP significantly protected the transcript levels
of SR genes in the CP hearts by 61% for RyR, 28% for SERCA2a, 61%
for PLB, and 41% for CQS. Results similar to these were obtained when
the CP hearts were preconditioning with three cycles of 5-min
ischemia and 5-min reperfusion (data not shown,
n = 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Previous reports have indicated that I/R and CP cause a significant decrease in cardiac performance and SR function (9, 26); moreover, I/R hearts showed a marked decrease in SR and non-SR genes (22, 25, 26). This study not only confirms changes in SR gene expression in I/R hearts but also provides evidence for the depression of mRNA levels for SR proteins such as RyR, SERCA2a, PLB, and CQS in CP hearts. Several investigators have also reported alterations in SR gene expression in cardiac hypertrophy and different types of heart failure (for a review, see Ref. 3) as well as stunned myocardium (7, 12). Because intracellular Ca2+ overload is known to occur in I/R hearts (25, 26) and hypoxia-reoxygenated hearts (24), it is possible that intracellular Ca2+ overload may produce alterations at the level of SR gene expression in I/R hearts. This view is supported by our observation that CP, which is known to result in the occurrence of intracellular Ca2+ overload and defects in SR function in hearts (1, 2), was found to produce changes in SR gene expression similar to those seen in I/R hearts. In fact, the decrease in the mRNA levels of SERCA2a and CQS in the CP heart was greater than those in the I/R heart. These results suggest that intracellular Ca2+ overload may be one of the possible mechanisms that may modulate the SR gene expression in I/R hearts. Oxidative stress has also been shown to explain the I/R-induced changes in heart function, subcellular activities, and SR gene expression (5, 25, 26), and thus it is difficult to indicate whether the observed mRNA changes in I/R and CP hearts are due to oxidative stress and Ca2+ overload.
The results described in this study show that IP not only attenuated
changes in SR gene expression in I/R hearts but also produced a similar
effect on alterations in SR gene expression in the CP hearts. The
I/R-induced alterations in cardiac performance, SR function, and mRNA
levels for SR genes were also prevented by different treatments such as
antioxidants (26) and 
-adrenergic receptor blockers
(25). Likewise, IP has been shown to be an effective
intervention for attenuating I/R-induced changes in infarct size,
arrhythmias, cardiac performance, and SR function (4, 8, 9, 15,
16, 19). Furthermore, IP has been documented to reduce the rise
in intracellular acidosis as well as intracellular Na+ and
Ca2+ concentrations due to I/R (21) in
addition to inhibiting glycolysis and maintaining glucose oxidation
(6). The results described in this study show that IP
itself depressed the transcript levels for SR proteins such as RyR,
SERCA2a, and PLB but not those of CQS. On the other hand, both I/R and
CP depressed the gene expression of the SR proteins to varying extents;
the changes observed due to IP were less severe than those observed due
to I/R and CP. Moreover, CP induced a more drastic decrease in mRNA
levels for SERCA2a and CQS compared with the changes induced by I/R.
Although these transcripts belong to the SR Ca2+-cycling
proteins, it is clear that IP, I/R, and CP affect these genes
disproportionately. These results indicate that, for yet unknown
reasons, SR genes are differentially regulated under different conditions. More studies are needed to investigate the transcription factors regulating the expression of each gene under different diseased
conditions. Studies conducted by Schaper and co-workers (7,
12) showed an increase in the transcript levels for SERCA2a, PLB, and CQS due to one cycle of 10-min coronary occlusion and 90-min
reperfusion (7), whereas two cycles of 10-min coronary occlusion followed by 60-min reperfusion under in vivo conditions showed a tendency toward a decrease in the mRNA levels. In fact, transcriptional modulation has been implicated as a major player in
alterations of SR gene expression in cardiac pathology
(12) as well as during cardiac differentiation and
myogenesis (13, 17). On the other hand, differential
changes in the mRNA stability cannot be ruled out.
Although IP caused a significant decrease in mRNA levels of the SR genes, these short episodes of IP were able to precondition SR genes against the deleterious effect of I/R- or CP-induced injury. The protection provided by three cycles of IP (3- or 5-min duration) was not surprising because IP cycles longer than 1 min were shown as essential to induce protection of SR protein perfusion (29). Under the experimental conditions employed in this study, we (10, 16) previously reported that the recovery in cardiac performance and SR function observed in I/R and CP hearts due to IP were related to the preserved protein content of SR Ca2+-cycling proteins. However, it is important to mention that the functional recovery of SR proteins may not be linked to the status of their gene expression (18) because the short duration of our experiment (30-min reperfusion) may not be sufficient to impart the expression of the corresponding proteins, and therefore the improvement in gene expression will not result in de novo protein synthesis in the heart. On the other hand, it is likely that IP may rescue the SR protein levels from degradation by Ca2+-dependent proteases that are activated during I/R (27). In this regard, it should be noted that one cycle of IP was found sufficient to reduce the elevation in the intracellular Ca2+ concentration in subsequent ischemic episodes (20). Thus it is noteworthy that, although Ca2+ overload, a common feature between I/R and CP, would lead to cell death, our study reports a novel finding regarding the potential of preconditioning in preserving the molecular structure of Ca2+-regulating organelles.
In conclusion, the major findings of this study were that 1) cardiac SR gene expression is depressed by IP, 2) intracellular Ca2+ overload may be a possible mechanism for inducing alterations in SR gene expression in the heart, and 3) IP was observed to attenuate changes in SR gene expression of the Ca2+-cycling proteins in both I/R and CP hearts.
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ACKNOWLEDGEMENTS |
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This study was supported by a grant from the Canadian Institutes of Health Research (CIHR Group in Experimental Cardiology).
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FOOTNOTES |
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10.1152/ajpheart.00447.2001
N. S. Dhalla holds the CIHR/Pharmaceutical Research and Development Chair in Cardiovascular Research supported by Merck Frosst Canada Incorporated. R. M. Temsah was a predoctoral fellow of the Heart and Stroke Foundation of Canada.
Address for reprint requests and other correspondence: N. S. Dhalla, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, 351 Taché Ave., Winnipeg, Manitoba, Canada R2H 2A6 (E-mail: cvso{at}sbrc.ca).
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 28 May 2001; accepted in final form 29 November 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 vs. I/R.
