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Ann Thorac Surg 1996;61:1407-1411
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Kinetics of Induction and Protective Effect of Heat-Shock Proteins After Cardioplegic Arrest

National Heart & Lung Institute, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, United Kingdom

Accepted for publication January 20, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Heat-shock proteins are known to enhance cardiac resistance to ischemia.

Methods. To evaluate the kinetics of heat-shock protein 70 in relation to its effect on postischemic recovery of cardiac mechanical (cardiac output) and endothelial function (as percentage increase of coronary flow in response to 5-hydroxytryptamine), isolated rat hearts were subjected to prolonged hypothermic cardioplegic arrest at different intervals ranging from 12 to 96 hours after heat stress (n = 6 in each interval).

Results. Immunoblotting showed the maximal level of heat-shock protein 70, 0.65 ± 0.10 (arbitrary units ± standard error of the mean), at 24 hours after heat shock and similar values at 26 and 30 hours (p= not significant). Postischemic recovery of cardiac output and endothelial function (percentage of preischemic value ± standard error of the mean) observed at 24 hours was 74.0 ± 2.4 and 58.3 ± 7.2, respectively. Similar values were observed at 26 and 30 hours (p = not significant).

Conclusions. In a protocol mimicking conditions for cardiac transplantation, postischemic recovery of cardiac output and endothelial function was improved when the interval between heat stress and ischemia ranged from 24 to 30 hours. This correlated with an apparently critical amount of heat-shock protein 70.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1411.

Heat-shock proteins (HSPs) belong to a large group of proteins with a wide range of molecular weights. Some HSPs are constitutively expressed, whereas others are induced by a variety of mechanisms but are preferentially expressed after heat shock [14]. Heat-shock proteins are known to protect the cell against a further stress.

Of particular interest is the finding that HSPs enhance cardiac resistance to ischemia. This has been demonstrated in numerous experimental models of low-flow or regional ischemia using different stress stimuli [4–7]. We [8, 9] have previously shown a protective effect of heat stress on both endothelial function and mechanical function after cardioplegic arrest. However, the exact time course of induction and the relation between the amount of HSP induced and the protective effect has not been adequately investigated, particularly after cardioplegic arrest [6, 7, 10].

The aim of the present study was to determine the levels of HSP 70 induction at various intervals after heat stress and to identify the amount of HSP affording the maximal recovery of endothelial and mechanical function in a protocol mimicking conditions for cardiac transplantation.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Sprague-Dawley rats weighing between 250 and 300 g were used in all experiments. Male rats were used to avoid a potential lack of homogeneity related to hormonal cycle. Six hearts were studied in each group. In all studies, animals received humane care in compliance with the ``Principles of Laboratory Animal Care'' formulated by the National Society for Medical Research and the ``Guide for the Care and Use of Laboratory Animals'' prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Rats were anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg) and then placed on a temperature-controlled heating pad (IMS K-Temp control unit; Concleton, Cheshire, England) set at 45°C until body temperature reached 42°C. Body temperature was monitored with a rectal temperature probe and maintained between 42° and 42.5°C for 15 minutes as previously described [10].

Experimental Preparation
The isolated, working rat heart preparation, which has been described in detail elsewhere [11], was used in this study. Briefly, in this left heart preparation, oxygenated Krebs-Henseleit bicarbonate buffer (NaCl, 118.5 mmol/L; NaHCO₃, 25 mmol/L; KCl, 4.75 mmol/L; MgSO₄, 1.19 mmol/L; KH₂PO₄, 1.18 mmol/L; CaCl₂, 2.5 mmol/L), pH 7.4, containing glucose (11.1 mmol/L) and gassed with 95% oxygen and 5% carbon dioxide at 37°C, enters the cannulated left atrium and passes into the left ventricle, from which it is spontaneously ejected through an aortic cannula against a hydrostatic pressure of 100 cm H₂O. The heart continues to eject as long as the pressure generated in the left ventricle is greater than 100 cm H₂O. Total cardiopulmonary bypass with maintained coronary perfusion can be simulated by clamping the left atrial cannula and introducing perfusion fluid at 37°C from a reservoir 100 cm above the heart.

Several variables, including cardiac output (CO), peak aortic pressure (PAP), and coronary flow (CF), are measured to reflect cardiac function. The most representative measurement of mechanical function is CO. Using this preparation, which is essentially that described by Langendorff, the heart continues to beat but does not perform external work. Ischemic cardiac arrest can be produced by clamping the aortic cannula. At this time, a cardioplegic solution is infused into a side-arm of the aortic cannula. During the ischemic period, the heart is maintained under hypothermia (4°C) by a cooling circuit. St. Thomas' Hospital cardioplegic solution No. 1, supplied as concentrate (David Bull Laboratories, Mulgrave, Victoria, Australia), was diluted in a Ringer's solution (Travenol Laboratories, Thetford, Norfolk, England) and passed through an 0.2-µm filter (Pall Biomedical, Glen Cove, NY).

Endothelial Function
Endothelial function was assessed through observations of preischemic and postischemic coronary flow responses to 5-hydroxytryptamine (5-HT). This vasodilatory response is endothelium dependent. In the intact endothelium, 5-HT causes vasodilation through the release of endothelium-derived relaxing factor, whereas in the presence of endothelial damage, it causes vasoconstriction by a direct effect on smooth muscle. Our protocol for this test was described in earlier studies [12].

After excision of the heart and aortic cannulation, Langendorff perfusion was initiated at 37°C. Coronary flow was monitored by an in-line electromagnetic flow probe (20-mL ECM2; Scalar, Delft, the Netherlands) proximal to the aortic cannula and connected to its compatible flowmeter (MDL 1401; Scalar). This provided an accurate (0.0 to 40.0 mL/min) digital readout of mean CF and a simultaneous hard-copy recording through a connection with a chart recorder (series 3000; Gould Electronics, Hainhault, Essex, England), which allowed accurate monitoring of steady-state conditions (less than 0.3 mL/min change in CF over 3 minutes).

After 9 to 13 minutes, the initial baseline CF was recorded. The Langendorff infusion was switched to one containing an additional 10^-5 mol/L 5-HT (Sigma Chemical Co, Poole, Dorset, England). The ensuing vasodilator response was monitored, and when the steady state had been reached (between 5 and 7 minutes), coronary flow was recorded. After this period, 5-HT was washed out by switching back to ordinary Krebs-Henseleit solution until a steady state had been reached (between 5 and 7 minutes). The heart was then subjected to a 10-mL hypothermic (4°C) infusion with the cardioplegic solution and maintained immersed in the same solution for 4 hours at 4°C. At the end of the ischemic period, the heart was reperfused in the Langendorff mode at 37°C for at least 15 minutes. When the baseline CF had been reestablished, the heart was again subjected to the same protocol of sequential infusion of 5-HT and Krebs-Henseleit solution as in the preischemic period.

Assessment of Heat-Shock Protein Expression
The induction of HSP 70 was assessed by SDS PAGE and Western immunoblotting as previously described [4, 9]. Proteins of whole-heart homogenates solubilized in 1% wt/vol SDS were separated on 10% SDS gels. Western blots on nitrocellulose membranes were probed with an antibody specific to inducible HSP 70 (Amersham). The result was visualized with peroxidase-conjugated secondary antibody and enhanced chemiluminescence. Hyperfilm MP was exposed to blots treated with enhanced chemiluminescence for 30 seconds and developed in an automatic film processor. After enhanced chemiluminescence, antibodies were removed from blots by incubation in a solution of 2% wt/vol SDS, 6.25% vol/vol 1 mol/L tris-HCL, pH 6.8, and 0.7% vol/vol 2-mercaptoethanol. Proteins were then visualized by staining with 0.01% amido black in a solution of methanol, water, and acetic acid (45:45:10 vol/vol). Amido black–stained blots and enhanced-chemiluminescence films were scanned using a Molecular Dynamics 300A laser densitometer, and HSP 70 levels were determined as a proportion of total protein loaded using the PDQUEST software package (PDI, Huntington, NY).

Experimental Time Course
Animals were anesthetized with halothane mixed with 95% oxygen plus 5% carbon dioxide and sacrificed at 12, 14, 16, 18, 20, 24, 30, 36, 48, and 96 hours after heat shock. In the control group, no procedure was performed. In the sham-operation group, animals were anesthetized without heat stress, allowed to recover for 24 hours, and then sacrificed.

The femoral vein was exposed, and heparin sodium (200 IU) was injected. One minute later, the heart was excised and immediately placed into cold (10°C) perfusion fluid. The aorta was cannulated, and Langendorff perfusion was initiated for a 3-minute washout period. Endothelial function studies were performed in the Langendorff mode (nonworking). Hearts designated to assess mechanical function were converted to a working mode preparation for 20 minutes, during which control values for aortic and coronary flow rates, CO (sum of aortic and coronary flows), and PAP were recorded. Any heart that did not reach a steady level of function with a stable heart rate and a CO greater than 65 mL/min was rejected. Two hearts were rejected, one because of a prolonged ischemic time in mounting it on the Langendorff apparatus and one because of a leak from incorrect manipulation.

At the end of the control period, the atrial and aortic cannulas were clamped, and the heart was immediately subjected to a coronary infusion of 10 mL of hypothermic (4°C) cardioplegic solution and maintained immersed in a state of hypothermic arrest for 4 hours. At the end of the ischemic arrest period, each heart was reperfused at 37°C in the Langendorff mode for 15 minutes and then converted to a 20-minute period of working mode at the end of which the recovery values of aortic and coronary flow rates and PAP were recorded.

Expression of Results
The postischemic recovery values of mechanical function and endothelial function were expressed as a percentage of the preischemic values. The level of HSP 70 was expressed in arbitrary units. An analysis of variance was performed with Scheffé's correction factor. The significance of differences between groups was determined with a nonpaired Student's t test, and significance was assumed when the p value was 0.05 or less. Values are given as the mean ± the standard error of the mean.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Mechanical and Endothelial Function
In the control group (n = 6), postischemic recovery (mean percentage of preischemic value) of CO, PAP, and CF was 57.0 ± 2.8, 63.4 ± 3.1, and 76.6 ± 3.6, respectively. Postischemic recovery of the coronary response to 5-HT (mean percentage of preischemic value ± standard error of the mean) was 20.3 ± 3.8.

Twenty-four hours after heat shock, postischemic recovery of CO, PAP, CF, and coronary flow response to 5-HT (as percentage of preischemic value ± standard error of the mean) was 74.0 ± 2.4, 79.3 ± 5.0, 89.8 ± 1.9, and 58.3 ± 7.2, respectively. Similar values (p = not significant) were seen at 26 and 30 hours after heat shock. Values obtained at 12, 14, 16, 18, and 20 hours after heat stress were similar to those in the control and sham-operation groups and significantly lower than those obtained at 24, 26, and 30 hours (p < 0.05). Likewise, values obtained after 30 hours were comparable to those in the control and sham-operation groups and significantly lower than those obtained at 24, 26, and 30 hours (p < 0.05). Table 1 and Figure 1 show the corresponding postischemic recoveries to the time intervals studied. Significance is reported in Figure 1. Table 2 shows the preischemic and postischemic values of CO, PAP, CF, and coronary flow response to 5-HT.

View larger version (34K): [in this window] [in a new window]   Fig 1. . Relation between level of heat-shock protein 70 (HSP 70) induced at different intervals and postischemic recovery of cardiac output (CO), peak aortic pressure (PAP), and coronary flow as well as vasodilatory effect of 5-hydroxytryptamine (5-HT), an index of endothelial function. Each point represents the mean of six hearts (± the standard error of the mean). Significant differences were as follows: a versus b and b versus c, both p < 0.05; a versus c, p = not significant; between values obtained within a, b, and c, p = not significant. (a = values obtained before 24 hours; b = values obtained at 24, 26, and 30 hours; c = values obtained after 30 hours; C = control.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The present study has shown that after prolonged cardioplegic arrest, the postischemic recovery of both cardiac mechanical function and endothelial function was significantly improved when the interval between heat stress and ischemia ranged from 24 to 30 hours. This interval correlated with the maximal heat-shock response as determined from levels of the inducible stress protein HSP 70.

When any cell is subjected to sublethal hyperthermia, a variety of adaptive modifications take place that serve to protect the cell from subsequent increases in temperature or other stresses [1–4]. In addition to hyperthermia, other stresses including ischemic preconditioning [13], chemical agents [14], and pressure overload [15] induce HSP synthesis. This suggests that the response may represent a generalized cellular defense mechanism and hence, the current concept of ``cross tolerance'' [6]. Because it uses an intrinsic cellular defense mechanism before the very onset of ischemia, this approach appeared to be an elegant therapeutic alternative to protect against cardiac ischemia [16]. Over the last decade, the protective effect of HSPs against ischemic damage has been widely investigated in various experimental models and has led to promising results in most studies.

However, some investigators [6, 13, 17] stressed the lack of correlation between the ``presence'' of HSPs and their protective role. This discrepancy suggests that a critical amount of HSP is necessary to elicit a protective effect and that this ``critical value'' is more important to define than the mere presence of HSPs. This is further emphasized by the possibility that each particular experimental model (animals, type of stress stimuli, length of ischemia, type of perfusion) might result in different ``critical protective'' concentrations of HSPs.

A temporal relationship between the appearance and subsequent disappearance of HSPs with functional recovery has been previously reported in nonquantitative HSP studies in the isolated rat heart subjected to low-flow ischemia [10] and after regional ischemia in the rabbit heart [7].

In the present study, we assessed the heat-shock response by measuring HSP 70 at different intervals ranging from 12 to 96 hours after heat stress using a semiquantitative method. In addition, for each interval, we evaluated the postischemic recovery of mechanical and endothelial function after prolonged cardioplegic arrest. Endothelial function was studied because in previous work, we [18] have demonstrated its influence on myocardial contractility. To date, there are no comparative data regarding induction of HSPs in the different cellular components. Our results strongly suggest that HSP 70 is induced in endothelial cells. This remains to be validated in isolated cell preparations.

We found that both maximal levels of HSP 70 as well as optimal recovery of mechanical and endothelial function were seen at 24, 26, and 30 hours. For all other intervals, the concentration of HSP 70 was significantly lower and was associated with a recovery similar to the control group (no heat stress). Thus, it appears that a critical amount of HSP is necessary to afford protection against ischemia.

This study has several limitations, which include the fact that although we have defined the relative amount of HSP 70 in relation to other proteins in the myocardium, we have not defined the absolute amount of HSP 70 in the cells concerned. In addition, we have chosen to study one type of HSP (HSP 70), the one that is most commonly expressed. Other HSPs could have similar or more important influence on myocardial protection. Finally, the clinical relevance of our results is influenced by the fact that the use of heat stress in the clinical setting is not practical. Other strategies for inducing HSPs need to be developed. It is hoped that the data presented here will be of value in understanding and possibly applying methods of enhancing the intrinsic protective mechanisms of the heart against ischemic damage.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Mr Jamal A. Amrani for help with the statistical analysis.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Prof Yacoub National Heart & Lung Institute, Heart Science Centre Harefield Hospital, Harfield Middlesex, UB9 6JH, United Kingdom.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Magdi H. Yacoub Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Amrani, M. Articles by Yacoub, M. H. Search for Related Content PubMed PubMed Citation Articles by Amrani, M. Articles by Yacoub, M. H. Related Collections Related Article