Ann Thorac Surg 1999;68:1736-1741
© 1999 The Society of Thoracic Surgeons
Original Articles
Myocardial self-preservative effect of heat shock protein 70 on an immature lamb heart
Fumikazu Nomura, MDa,
Mitsuru Aoki, MDa,
Joseph M. Forbess, MDa,
John E. Mayer, Jr, MDa
a Department of Cardiovascular Surgery, Children’s Hospital, Boston, Massachusetts, USA
Address reprint requests to Dr Nomura, Department of Cardiovascular Surgery, Kure National Hospital, 3-1, Aoyama, Kure Hiroshima, 737, Japan
e-mail: fnomura{at}kure-nh.go.jp
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Abstract
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Background. Heat shock proteins have been shown to enhance myocardial tolerance of ischemia-reperfusion injury and are induced in the myocardium of many animals by various stressors.
Methods. To assess the effects and time course of the inducible form of heat shock protein 70, we raised the rectal temperature of 15 neonatal lambs to 43°C for 15 minutes. At 15, 30, 60, and 120 minutes and 24 hours after heat shock, hearts were subjected to immunoblot analysis for heat shock protein (hsp 72/73). Twenty-four hours after heat shock, neonatal lamb hearts (n = 8) were subjected to 2 hours of cold cardioplegic ischemia (HSP group). Eight neonatal lamb hearts without heat shock served as control. After 60 minutes of reperfusion, left ventricular systolic and diastolic function, coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and lactate levels were measured. Endothelial function was assessed by measuring in situ coronary vascular resistance response to acetylcholine and trinitroglycerine.
Results. The HSP group showed a significantly higher recovery of systolic function as well as MVO2, and a lower lactate level compared to the control group at 60 minutes after reperfusion. Recovery of coronary endothelial function was also significantly better in the HSP group than in the control group. Inducible form of HSP 70 was expressed 15 minutes after heat shock and continued to be observed at 24 hours after the stress.
Conclusions. Heat shock stress associated with the production of inducible heat shock proteins improved the recovery of ventricular function as well as endothelial function and aerobic metabolism after hypothermic cardioplegic ischemia. Induction of heat shock proteins by any means prior to planned hypothermic ischemia may lead to a new approach for myocardial protection.
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Introduction
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In response to adverse environmental changes, cells from many organisms increase the expression of a class of proteins refered to as heat shock or stress proteins. When cultured cells or whole organisms are exposed to elevated temperatures, they respond by synthesizing a small number of highly conserved proteins, the heat shock proteins. Although first noted by Ritossa [1] in 1962 in the fruit fly, Drosophila busckii, this response appears to be ubiquitous, as it has been observed in every organism in which it has been sought, including yeast, bacteria, soybeans, and humans [2]. These proteins are induced by a wide variety of stressors and seem to have broad protective functions that might affect normal growth and development [3]. Other treatments reported to induce the production of stress proteins include anoxia or ischemia [4], pressure and volume overload [5], and hydrogen peroxide [6].
Recent studies have detected the 70-kDa family of heat shock proteins (hsp 70) in neonatal and adult heart tissues of many species, including dog [7], rat [4], and rabbit [8]. Synthesis of these proteins is increased by exposure to elevated temperatures. Currie and associates [9] showed that exposure of rats to elevated temperatures, which induced cardiac heat shock protein, resulted in improved recovery of contractile function after subsequent ischemia and reperfusion. This study explored the induction time course and the protective effect of hsp 70 against hypothermic cardioplegic ischemic insult.
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Material and methods
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We prepared two sets of protocols. The first was for protein analysis and the second for mechanical function evaluation.
Protocol 1
Experimental group
Lambs used in this protocol weighed from 2.4 to 6.5 kg and were 2 to 7 days old. The two groups in this protocol were the heat shock protein (HSP) group and control group. In the HSP group (n = 15), at 24 hours before cardioplegic arrest, lambs were lightly anesthetized with 20 mg/kg of ketamine and bathed in a circulating hot water bath (45°C) for 30 minutes to elevate the body temperature and maintain a rectal temperature of 43°C for 15 minutes. Seven hearts from the HSP group underwent protein analysis. The hearts were excised while the lambs were anesthetized with 40 mg/kg of ketamine at 15 minutes (n = 1), 30 minutes (n = 1), 60 minutes (n = 1), 120 minutes (n = 1), and 24 hours (n = 3) after heat shock stress. Western blot analysis for hsp 70 was then performed. Three hearts from the control group were subjected to western blot analysis for hsp 70 as a control for protein analysis.
Preparation for heat shock protein 70 analysis
Left ventricular muscle specimens were rapidly frozen in liquid nitrogen. For preparation of myocardial proteins, approximately 1.6 g of myocardium was homogenized with polytion homogenizer in 10 mL of phosphate-buffered saline (pH 7.2) in the presence of 0.25 mmol/L tosyl-lysin chloromethyl keton, 0.25 mmol/L tosylamide-2 phenylethychoromethyl keton, 20 g/mL leupeptin, 0.5 mmol/L phenylmethylsulfenyl fluoride (PMSF), or 25 g/mL benezamidine and aprotinin. Homogenized tissues were aloquoted and diluted 1:10 (16 µg/mL) with an electrophoresis sample buffer containing 4% sodium dodecyl sulfate (SDS) in the presence of dithiothreitol. Samples were boiled at 95°C for 10 minutes, centrifuged at 12,000 x g for 5 minutes, then frozen at -20°C until used for electrophoresis [10].
Electrophoresis using phastsystems
Application of the samples and electrophoresis procedure was performed according to the commercial instruction manual (Pharmacia, Fine Chemicals, Uppsala, Sweden). The amount of tissue protein loaded into Phastgel was 8 µg. Phastgels with an SDS-polyacrylamide gradient were used. Applicator combs were modified to a two single wells format. SDS-polyacrylamide gel electrophoresis was routinely run for 95 V/h.
Phast transfer of separated proteins
Semidry electrophoretic transfer of proteins was performed after peeling the SDS-polyacrylamide electrophoresis gel from the polyester backing and placing the gel on an immobilizing membrane as previously described [11]. The transfer generally used the Tris/glycine buffer and a current of 25 mA/gel. The transfer time normally required 10 to 20 minutes. The polyvinylide difluoride (PDDF) (Bio-Rad, Richmond, CA) membrane was blocked with 0.1% nonfat milk powder, 0.005% Tween-20 in phosphate-buffered saline (pH 7.2) for 1 hour at 27°C.
Channel western blotting
Detection of the transferred proteins by western blotting was done by using a channel blotter specially designed for use with the PhastTransfer System (Miniblotter; Immunetics, Cambridge, MA). Mouse monoclonal antibody specific for both constitutive and inducible (N27F3-4 for hsp 72 and 73 kDa) and only inducible (C92F3A-5 for hsp 72 kDa) forms of heat shock proteins were purchased from Stress Gen Biotechnologies Corp (Victoria, Canada) and used as 1:2,000 dilution per channel for 40 minutes. Membranes were washed three times for 5 minutes each and then incubated with goat anti-mouse alkaline phosphatan (South Biotechnology, Birmingham, AL) at 1:1,500 dilution for 30 minutes. Prestained molecular weight standards were purchased from Integrated Separation System (Natick, MA).
Protocol 2
Experimental preparation for functional evaluation
An isolated blood perfused heart model [12, 13] was used for studying 16 hearts from neonatal lambs (HSP group n = 8, control group n = 8). All lambs in both groups were anesthetized with intramuscular ketamine (40 mg/kg), intubated, and placed on a respirator with inhalation of a 1:1 mixture of oxygen and nitrous oxide and 0.5% halothane. Through a median sternotomy, the arterial cannula with a blood pressure monitoring port was inserted into the brachiocephalic artery after systemic heparinization (2,000 units). Coronary perfusion was established with a roller pump (Coronary Perfusion Pump; Olson Medical Products Inc, Ashland, MA) and oxygenator system (Bio-2; American Bentley, Irvine, CA) before isolation, providing no period of ischemia. After insertion of a left ventricular (LV) vent at the apex, the heart was isolated and placed in a temperature-controlled water bath. Both superior and inferior cavas were ligated, and coronary venous return was drained from a cannula inserted into the right ventricle through the pulmonary artery. A sampling catheter was placed in the coronary sinus through the hemiazygos vein for coronary venous blood gas analysis. Heparinized fresh homologous blood was used as the perfusate, and it was oxygenated with a mixture of 20% oxygen, 5% carbon dioxide, and 75% nitrogen by using a bubble oxygenator. The arterial pH was maintained at 7.4 with sodium bicarbonate (corrected to perfusate temperature). Serum potassium and ionized calcium were maintained at 4 to 5 mEq/L and 1.0 mEq/L, respectively.
The temperature of perfusate, water bath, and myocardium were monitored by thermal probes, and the perfusate and water bath were maintained at 37°C by a heater circulator (Model 1252-00; Cole-Parmer Instrument Co, Chicago, IL) except during the hypothermic phase that was brought on by circulating ice water. Coronary perfusion pressure was maintained constantly at 60 mm Hg, except during the cooling and reperfusion periods. A latex balloon with pressure transducer (SPC-350; Millar Instruments Inc, Houston, TX) was placed inside the LV through the apex to measure the LV function. A Foley balloon catheter (10 F) was inserted in the left atrium to prevent the LV balloon from herniating into the left atrium and to vent blood as well as air from the LV.
Measurements
LV function was measured 60 minutes after reperfusion during isovolumic contraction by inflating the intraventricular balloon with 0.5-mL increments of saline until an LV end-diastolic pressure of 20 mm Hg was reached. Left ventricular pressure and its first derivative (dp/dt) were recorded at each volume. The recovery of systolic function was evaluated by measuring the maximum developed pressure (max DP), positive maximum LV dp/dt, peak DP at a constant balloon volume (v10), and peak dp/dt at v10. The volume, v10, was defined as the balloon volume to produce an end-diastolic pressure of 10 mm Hg during preischemic baseline measurements. Negative maximum dp/dt was measured before and after ischemia to assess the diastolic functional recovery.
Coronary blood flow (CBF) was measured continuously by an inline electromagnetic flow meter (MFV-3100; Nihon Kohden, Tokyo, Japan) connected to the venous cannula. This flow was considered to represent total coronary blood flow.
Myocardial oxygen consumption (MVO2) was measured before ischemia, and at 15, 20, 30, and 60 minutes after reperfusion. Arterial and venous bloods were collected during the beating but nonworking state. The hemoglobin concentration and the oxygen saturation were measured with a blood gas analyzer (Corning Model 280; Ciba-Corning, Medfield, MA) and corrected for temperature and pH. Oxygen consumption was calculated using the following equations and derived values:
Arterial lactate (mmol/L) was measured at baseline and 15, 30, and 60 minutes after reperfusion, which represented the lactate extraction or production by the heart in our perfusion model.
Coronary endothelial function was assessed by the coronary vascular resistance response to acetylcholine infusion as described previously [13]. A vasodilator response to acetylcholine is dependent on the release of endothelium-derived relaxing factor. Acetylcholine was infused for 30 seconds into the arterial cannula at rates calculated to achieve an arterial concentration of 10-7 mol/L. Maximum decrease in coronary vascular resistance during the acetylcholine infusion, divided by baseline coronary vascular resistance response was used to assess the endothelium-dependent vascular capacity. Trinitroglycerin (3 x 10-5 mol/L) was infused in the same way, and the response of coronary vascular resistance to infusion of trinitroglycerin was used to assess nonendothelium-dependent vasodilator capacity. The pump perfusion flow was not changed during these infusions. Both LV function and coronary endothelial function were measured before ischemia and 30 minutes after reperfusion.
Experimental protocol for functional evaluation
Baseline measurements were made after a 20-minute equilibrium period. Then both the perfusate and water bath were cooled to 15°C. At 10 minutes after cooling, when the myocardial temperature reached 15°C, the heart was subjected to cold cardioplegic ischemic arrest by infusion of 20 mL/kg body weight of cardioplegic solution for 2 minutes followed by topical cooling (myocardial temperature was maintained at 10°C). A second dose of 10 mL/kg was given after 60 minutes. The composition of cardioplegic solution was 0.45% sodium chloride and 2.5% dextrose solution with 20 mEq/L of potassium chloride and 6 mEq/L of sodium bicarbonate (pH 7.4 at 37°C, 360 mOsm/L). Reperfusion began with the perfusate at room temperature (25°C) and then gradually rewarmed to normothermia for 25 minutes. Mean coronary perfusion pressure was maintained at 20 mm Hg during the first 5 minutes, increased to 40 mm Hg during the second 5 minutes, and then was kept at 60 mm Hg until the end of the experiment [12, 13]. During the first 15 minutes of the reperfusion period, the oxygenator was bubbled with high oxygen (95% oxygen and 5% carbon dioxide) to imitate the arterial blood gas conditions of clinical cases. Thereafter the gas was changed to 20% oxygen, 5% carbon dioxide, and 75% nitrogen.
Animals used in this study received humane care in compliance with the "Principles of Laboratory Animal Care" prepared 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 no. 80-23, revised 1985).
Statistics
All values were expressed as mean ± standard deviation and analyzed by a statistical analysis system (SPSS, SPSS Inc, Chicago, IL). One-way analysis of variance was used to compare the differences in recovery between the groups. Results were further compared using Student’s t test. A p value less than 0.05 was considered significant.
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Results
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There were no significant differences in heart rate, CBF, MVO2, max DP, maximum dp/dt, maximum developed pressure at v10, and peak dp/dt at v10 between the groups (Table 1).
The 70-kDa heat shock protein family includes 72-kDa (inducible) and 73-kDa (constitutive) proteins. The constitutive protein hsp 73 was present in both the control group and heat shocked hearts (Fig 1). At 15 minutes after heat shock stress, the hearts expressed the inducible heat shock protein hsp 72 as well as at 30, 60, and 120 minutes after heat shock. Furthermore, they continued to express this inducible protein for at least 24 hours after the stress.
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Fig 1. Western blot analysis for heat shock protein (hsp) 70 from the left ventricle specimen of a control heart at 15, 30, 60, and 120 minutes, and 24 hours after heat shock. (lanes a) N27F3-4 antibody reacted with both inducible (hsp 72) and constitutive (hsp 73) heat shock proteins. (lanes b) C92F3A-5 antibody reacted with only the inducible heat shock protein (hsp 72). Control showed only constitutive hsp 73, whereas all heat shocked left ventricles expressed both inducible hsp 72 and constitutive hsp 73. Prestained markers weighing approximately 20, 29, 39, 68, and 95 kDa were loaded for marking.
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Functional recovery in the HSP group was greater than in the control group at 60 minutes after reperfusion (Table 2). Developed pressure (p = 0.023), maximum dp/dt (p = 0.017), DP v10 (p = 0.017), and peak dp/dt v10 (p = 0.031) showed a higher percentage recovery in the HSP group compared with the control group after 60 minutes of reperfusion.
There was no significant difference in heart rate between the groups during reperfusion up to 60 minutes (Table 3). There was no significant difference in percentage recovery of CBF during reperfusion between groups (Table 4). Coronary blood flow reached 150% of baseline at 15 minutes of reperfusion and continued to be higher than baseline.
Our results showed insufficient recovery of MVO2 in the control group (at 60 minutes, 57.1% ± 17.6%), whereas the HSP group recovered to baseline at 15 minutes of reperfusion, therefore the groups were significantly different at 60 minutes (p = 0.008) (Table 5).
Changes in arterial lactate level were considered to reflect the lactate production from the heart because no other organ was used in our isolated perfusion model. Lactate levels at baseline were 3.20 ± 0.63 mmol/L (n = 4) in the control group and 3.07 ± 0.81 mmol/L (n = 8) in the HSP group (p > 0.05; Table 6). Lactate production, compared with baseline levels in the control group, was higher in the HSP group at 15 and 60 minutes after reperfusion (p = 0.049, 0.0081, respectively).
Recovery of the coronary vascular resistance response to the infusion of acetylcholine at 30 minutes of reperfusion was significantly better in HSP group than in the control group (Table 7). However, the HSP group showed the same degree of recovery of coronary vascular resistance response for trinitroglycerin infusion at 30 minutes of reperfusion.
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Comment
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Recently, new means of protecting the myocardium have been described, which are based on the understanding of inherent cellular means of self-preservation [14]. The enhancement of this self-preservative capacity could lead to more effective cardiac tolerance of ischemia and further advanced myocardial protection. These phenomena are known as ischemic preconditioning [15] and stress protein synthesis.
It has been shown that hyperthermia induces the synthesis of a small group of proteins known as heat shock or stress proteins in the heart and other tissues. Cells that are subjected to such stress accumulate these heat shock proteins [16] and acquire a transient resistance to subsequent exposure to stress. A heat shock protein is reported to be a self-preservation protein that is induced to maintain cell homeostasis against various forms of stress. The hsp 70 family is constitutively present in normal and unstressed cells in a form called constitutive hsp 73, whereas the heat shock proteins induced in cells experiencing stress are called inducible hsp 72. We demonstrated that these inducible proteins were expressed even at 15 minutes of total body hyperthermia, which is similar to the findings of Liu and associates [17], and continued to be expressed for at least 24 hours after insult. With our isolated heart model, we eliminated the hormonal effects of the heated animal and purely evaluated heat shocked hearts.
Karmazyn and colleagues [18] showed that exposure of rats to elevated temperature in which cardiac heat shock protein was induced resulted in improved recovery of contractile function after subsequent ischemia and reperfusion. Furthermore, reperfusion damage, as measured by creatine kinase release, was reduced significantly in the heat shocked hearts. They also noted that levels of endogenous catalase, the hydroxyl radical scavenger, were increased significantly in the heat shock protected animals compared with controls. We observed positive results similar to theirs by using a blood perfused isolated neonatal lamb heart model after 120 minutes of hypothermic cardioplegic ischemia. We also observed significantly better postischemic functional recovery.
We also demonstrated that endothelial function as measured by acetylcholine response was well preserved in heat shocked hearts, which supports the hypothesis of a link between stress proteins and endothelial-derived relaxing factor (EDRF) [19]. The protective effect of stress proteins might be linked to the protective effect of EDRF. The coronary endothelium has a significant effect on cardiac physiology and pathophysiology, and whole-body heat stress is reported to induce hsp 70 in endothelial cells [20]. Enhanced myocardial tolerance with hsp 70 might be acquired not only through enhanced tolerance of cardiomyocytes but also through the preservation of the coronary endothelium [13]. Yellon and associates [8] showed less oxidative stress in the heat shock group, as measured by levels of oxidized glutathione, compared with controls (in the setting of low flow ischemia in a perfused rabbit heart model). Polla [6] postulated that heat shock proteins might have a direct antioxidant effect and that hsp 70 might be cardioprotective by directly or indirectly quenching superoxide free radicals. Heat shock proteins may directly protect the myocardium by their known ability to cause folding, unfolding, and translocation of protein complexes (a chaperone function) [3, 17, 21]. It is also probable that the primary effect might involve a link between heat shock and oxygen free radicals [22].
Although the exact mechanisms are still unknown, the heat shocked hearts produced less lactate than the control hearts after reperfusion, which suggests that the protection afforded by heat shock was associated with a marked slowing of ischemic metabolism during ischemia or rapid recovery of aerobic metabolism during early reperfusion. This result was consistent with the energy metabolism in ischemic preconditioning [23].
Thornton and associates [24] reported that ischemia preconditioning lasted only 120 minutes after the first ischemic conditioning. However, Marber and coworkers [25] recently reported that there was another window at 24 hours after ischemic preconditioning as well as heat stress. Although these mechanisms of preconditioning are still unclear, we speculate that the protective effect seen with ischemic preconditioning might be closely related to the protective phenomenon of heat shock protein synthesis.
In conclusion, a brief period of heat shock improved the recovery of ventricular function as well as endothelial function after ischemia and reperfusion. The beneficial effect of heat shock might involve the attenuation of endothelial damage during ischemia and reperfusion. Induction of hsp 70 by systemic hyperthermia or other means before planned hypothermic ischemia could further improve myocardial protection in clinical settings by this self-preservation system against ischemia-reperfusion insult. Thus, methods to induce this protein, including systemic hyperthermia, could lead to a new era of myocardial protection.
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Acknowledgments
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We thank Mark A. Cioffi, MAT for technical assistance and Dennis Bergau for refining the manuscripts.
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References
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Accepted for publication April 12, 1999.
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Abstract
Introduction
