(Circulation. 1996;94:2185-2192.)
© 1996 American Heart Association, Inc.
Articles |
Reperfusion Causes Significant Activation of Heat Shock Transcription Factor 1 in Ischemic Rat Heart
the Department of Cardiovascular Surgery, Faculty of Medicine (J.N., S.N., K.M., T.B.), and Department of Cell Biology, Chest Disease Research Institute (J.N., A.N., T.H., M.T., K.N.), Kyoto University, Kyoto, Japan.
Correspondence to Kazuhiro Nagata, PhD, Department of Cell Biology, Chest Disease Research Institute, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan. E-mail nagata@chest.chest.kyoto-u.ac.jp.
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Abstract |
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Background The myocardial protective role of heat shock protein (HSP) has been demonstrated, and there has been increasing interest in stress response in the heart. We examined the DNA-binding activity of heat shock transcription factor (HSF), by which the transcription of heat shock genes is mainly regulated, during heat shock or ischemia/reperfusion in isolated rat heart.
Methods and Results Rat hearts were isolated and perfused with Krebs-Henseleit buffer by the Langendorff method. Whole-cell extracts were prepared for gel mobility shift assay using oligonucleotides containing the heat shock element, which is present upstream of all heat shock genes. Induction of mRNAs for HSP70, HSP90, and GRP78 (glucose-regulated protein) was examined by Northern blot analysis. Although the activation of HSF during global ischemia was weak and rapidly attenuated, postischemic reperfusion induced a significant activation of HSF. In addition, although HSP70 mRNA was hardly induced during ischemia, its burst induction was detected during postischemic reperfusion. Supershift assays using specific antisera for HSF1 and HSF2 revealed that ischemia/reperfusion as well as heat shock induced the activation of HSF1 in hearts. Although the expression of HSP70 mRNA during heat shock was more vigorous than the expression during ischemia/reperfusion, the induction of HSP90 mRNA in postischemic reperfusion was significantly greater than that in heat shock.
Conclusions Our findings demonstrated that reperfusion causes a significant activation of HSF1 in ischemia-reperfused heart. The striking contrast between the induction of HSP70 mRNA and that of HSP90 mRNA suggests the presence of regulatory mechanisms other than HSF.
Key Words: heat shock factor • stress response • ischemia • reperfusion • myocardium
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Introduction |
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All organisms, from bacteria to humans, respond to hyperthermia or other physiological stresses that are unfavorable to their survival through the induction of a group of protective proteins termed heat shock, or stress, proteins. These proteins are highly conserved throughout evolution and play essential roles as molecular chaperones under unstressed conditions as well as under stressed conditions by facilitating the folding, intracellular transport, assembly, and disassembly of other cellular proteins.1
The heat shock/stress response is mainly mediated at the transcriptional level by the activation of a preexisting transcription activator, HSF. HSF binds to HSE, which is present upstream of all heat shock genes and is composed of at least three pentanucleotide modules (nGAAn; n indicates any nucleotide) arranged as contiguous inverted repeats.2 Recent studies have identified a family of HSFs in vertebrate cells and suggested that functional differences exist among the members of HSFs.3 4 5 6 Under stress conditions such as heat shock or exposure to heavy metals and amino acid analogues, HSF1 induces heat shock gene transcription through its trimerization and translocation into the nucleus and, thus, acquisition of the DNA-binding activity.7 8 The activation of HSF2 is induced during erythroid differentiation of human K562 erythroleukemia cells with hemin treatment.9
In the heart, induction of stress response has been observed under various physiological stresses, such as ischemia,10 11 12 13 trauma,14 hemodynamic overload,15 16 and exercise,17 as well as hyperthermia. Induction of HSPs by pretreatment with heat shock or ischemia has been shown to be correlated with improvement of functional recovery18 19 20 and reduction of infarct size21 22 23 after heart ischemia. Furthermore, these protective roles were demonstrated in transgenic mouse overexpressing HSP70 in the heart.24 25 It is apparent that at least HSP70 plays a direct role for myocardial protection against ischemia. Thus, there has been increasing interest in the heat shock/stress response in the heart. However, the molecular mechanisms regulating this response in the heart remain unknown.
On the other hand, numerous studies of postischemic reperfusion damage in hearts have been reported because of its great importance in the treatment of ischemic heart disease or cardiac surgery as well as in the etiology of this disease.26 Despite the potential prospect for reperfusion as an effective means of myocardial salvage, evidence obtained in clinical situations and under various experimental conditions has revealed a detrimental influence of reperfusion on the myocardium.
In the present study, we examined the HSF activation by gel mobility shift assay during ischemia or postischemic reperfusion as well as heat shock in isolated rat heart. In this assay, HSF activation is observed immediately after the onset of the stimulus. We demonstrated that postischemic reperfusion rather than ischemia induced the heat shock or stress response in global ischemia and that HSF1 mainly mediated the stress response in the ischemia-reperfused heart. We also examined the contrast between HSP70 and HSP90 in mRNA induction in response to heat shock or ischemia/reperfusion.
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Methods |
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Isolated Heart Perfusion
Male Sprague-Dawley rats (250 to 300 g; Shimizu Laboratory Supplies) were anesthetized with diethyl ether and administered heparin (200 IU IV). The hearts were rapidly excised, and the ascending aorta was cannulated. The hearts were then perfused by the Langendorff method with Krebs-Henseleit buffer consisting of (in mmol/L) NaCl 118, NaHCO3 25, KCl 4.6, MgSO4 1.2, KH2PO4 1.2, CaCl2 2.5, and glucose 11 at 37°C at a constant pressure of 100 cm H2O. Perfusion was initiated within 20 seconds after the excision of the hearts. The perfusate was bubbled with 95% O2/5% CO2 gas, and pH of the buffer was 7.4. The temperature of the perfusion buffer measured at the aortic cannula was maintained at 37°C (or 42°C during the heat shock period), and the hearts were contained in a water-jacketed chamber at the same temperature. LV pressure and LV dP/dt were monitored through the use of a fluid-filled latex balloon inserted into the LV via the left atrium and connected to a pressure transducer. All the recordings were made with a four-channel recorder (model RJG-4124, Nihon Kohden). The balloon volume was adjusted to obtain an LVEDP of 5 to 9 mm Hg. The LVDP was calculated as the difference between the peak systolic and end-diastolic pressures. Coronary flow was measured by timed collection of the overflow from the hearts. The CK concentration was determined according to the spectrophotometric method of Rosalki.27
After a 30-minute stabilization, baseline hemodynamic measurements were made. Then, in the heat shock experiments, warm (42°C) buffer was perfused for the indicated time periods. In the ischemia/reperfusion experiments, isolated hearts were subjected to 2- to 40-minute global ischemia by clamping the aortic cannula with or without reperfusion. Throughout the ischemic period only, the intraventricular balloon was kept deflated. Postischemic reperfusion was applied under the same conditions as during stabilization. Control hearts were perfused with 37°C buffer after excision. These experimental protocols are summarized in Fig 1
. Hearts that developed ventricular fibrillation and did not return to normal sinus rhythm were excluded from the data analysis. At the end of each experiment, the ventricular tissue was quickly frozen in liquid nitrogen and then stored at -80°C. All of these experiments were performed under conditions in compliance with the National Institutes of Health guidelines on the care and use of laboratory animals.
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Cell Culture
REF cells were prepared and maintained in Dulbecco's modified Eagle's medium containing 10% fetal calf serum at 37°C in 5% CO2.28 Heat shock treatment was carried out by submerging a sealed culture dish in a 43°C water bath for 1 hour.
Preparation of Cell Extracts
To prepare whole-cell extracts from the hearts, the frozen samples were crushed and homogenized with a Polytron homogenizer (Kinematica) in high-salt buffer28 (20 mmol/L HEPES, pH 7.9, 25% glycerol, 0.42 mol NaCl, 1.5 mmol/L MgCl2, 0.2 mmol/L EDTA, 0.5 mmol/L phenylmethylsulfonyl fluoride, 1 µg/mL leupeptin, 1 µg/mL pepstatin A, and 0.5 mmol/L dithiothreitol). The lysates were kept on ice for 5 minutes and then centrifuged at 100 000g for 5 minutes at 4°C. The supernatants were frozen in liquid nitrogen and stored at -80°C. Whole-cell extracts for the REF cells were prepared as described previously.29
Gel Mobility Shift Assay
Whole-cell extracts from the hearts and REF cells were assayed by gel mobility shift assay as described previously,3 using a double-stranded synthetic HSE carrying four inverted nGAAn repeats (5'-CTAGAAGCTTCTAGAAGCTTCTAG-3'). Binding reactions with protein extracts (40 µg for heart extracts or 5 µg for REF cell extracts) were performed for 20 minutes at 25°C in 25 µL of binding buffer (10 mmol/L Tris, pH 7.5, 50 mmol/L NaCl, 1 mmol/L EDTA, and 5% glycerol) containing 0.2 ng of 32P-labeled probe and 0.5 µg of poly(dI-dC)·poly(dI-dC) (Pharmacia Biotech). The samples were then electrophoresed on a nondenaturing 4% polyacrylamide gel, dried, and autoradiographed. For competition experiments, binding reaction mixtures contained a 10- or 100-fold molar excess of unlabeled HSE oligonucleotides or a 100-fold molar excess of unlabeled CREB or NF-
B oligonucleotides (5'-AGAGATTGCCTGACGTCAGAGAGCTAG-3' for CREB, and 5'-AGTTGAGGGGACTTTCCCAGGC-3' for NF-B; Promega Corp). For antibody supershift experiments, 0.5 to 1.0 µL of diluted (1:10 with PBS) specific antisera raised against recombinant chicken HSF1 (
HSF1ß) or HSF2 (HSF2
) was added to whole-cell extracts and incubated for 20 minutes on ice before the binding reaction.29
RNA Isolation and Northern Blot Analysis
Total RNA was isolated from the tissues by acid guanidinium thiocyanate-phenol-chloroform extraction.30 Total RNA (10 µg/lane) was separated on 1% agarose-formaldehyde gel and then transferred to a nylon membrane (Gene Screen Plus, DuPont-New England Nuclear). The filter was hybridized with the 32P-labeled probes and washed as previously described.31 The probe was removed from the filter after being boiled for 20 minutes in a buffer containing 1% SDS and then rehybridized with another probe. The probes were as follows: the genomic DNA probe for human HSP70, a BamHI/HindIII fragment of pH 2.3 (a gift from Dr R.I. Morimoto, Northwestern University),32 cDNA probes for human HSP90, a Pst I/BamHI fragment of pC-11R (a gift from Dr K. Yokoyama, Riken Tsukuba Life Science Center, Ibaraki, Japan),33 for human GRP78, a BamHI/EcoRI fragment of pHG2 (a gift from Dr R.I. Morimoto),34 and for mouse ß-actin, an EcoRI fragment of pMAß-3'ut (a gift from Dr S. Sakiyama, Chiba Cancer Center Research Institute, Chiba, Japan)35 as an internal control. Isolated inserts were labeled with [32P]dCTP using the random primer kit (Boehringer-Mannheim). The radioactivity hybridizing to each mRNA was determined by exposing the hybridized filter to an imaging plate and scanning the plate with a bioimage analyzer (GS-250, BioRad). The relative radioactivity of each signal was normalized to ß-actin and compared with that of 30-minute control.
Statistical Analysis
All values are expressed as mean±SEM. Statistical comparisons between the hemodynamic time points were assessed for significance with one-way ANOVA followed by Bonferroni's test. Comparisons were performed between control and heat-shocked or ischemia-reperfused hearts at individual time points by using the unpaired t test. Statistical significance was defined as P<.05.
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Results |
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The changes of hemodynamic parameters and CK release during 42°C heat shock (Table 1
) and reperfusion after 20-minute global ischemia (Table 2) are summarized. In heat-shocked hearts, heart rate and coronary flow were increased, and LVDP was decreased. In ischemia-reperfused hearts, ischemia produced a total reduction in all hemodynamic parameters. In the heat-shocked heart, CK efflux was only approximately twofold and approximately fourfold of baseline level at 10 and 60 minutes, respectively. On the other hand, in the ischemia-reperfused heart, CK efflux was increased to a level 
34 times the baseline at 10-minute reperfusion. In both experiments, there was no significant difference between baseline data.
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All of the experiments were repeated using at least three rats, and the representative data of reproducible results are shown.
Activation of HSF During Heat Shock
The HSE-binding activities of HSF in control or heat-shocked REF cells and in rat hearts were examined at the indicated time points during 42°C heat shock by gel mobility shift assays using an end-labeled HSE oligonucleotide as a probe (Fig 2). No HSF activation was detected in control REF cells (lane 11), whereas significant activation was observed in heat-shocked REF cells (lane 12). In hearts, a faint HSE-binding activity, which was observed in controls (lanes 1 and 2), began to increase at 5 minutes (lane 3) and reached a peak at 20 minutes of heat shock (lane 5). HSF continued to be active until 120 minutes (lanes 6 to 9), and then its activity was attenuated (lane 10). The HSF/HSE complex consists of multiple bands. Previous studies have indicated that HSP70 is a component of some of these multiple bands and suggested that activated HSF might associate with HSP70 or other proteins.36 37 Comparison of the mobility of the activated HSF in lysates of REF cells and rat hearts suggests differences in its complex formation. An additional band, which migrates faster than the HSF/HSE complex, was detectable. This band was believed to represent nonspecific bindings.
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Activation of HSF During Global Ischemia
To examine HSF activation during ischemia, HSE-binding activities of whole-cell extracts from hearts, which were subjected to global ischemia by clamping the aortic cannula after the stabilization, were analyzed by gel mobility shift assay. The activation of HSF during global ischemia began to be detected at 3 minutes after clamping (Fig 3, lane 4). The HSF activity reached a peak at 6 minutes (lane 5) and was then attenuated (lanes 7 to 9). The induced HSE-binding activity of HSF during global ischemia was significantly weaker than that during heat shock (compare lane 2 with lane 5).
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Activation of HSF During Postischemic Reperfusion
After global ischemia for 10 to 40 minutes, the hearts were reperfused for the indicated periods under the same conditions as during stabilization, and the HSE-binding activities were determined by gel mobility shift assay (Fig 4A). The relative binding activities during global ischemia or reperfusion after 20-minute ischemia were estimated using a bioimage analyzer and normalized to the maximum level as shown in Fig 4B. After 10-minute ischemia, the HSE-binding activity was induced (Fig 3
, lane 6; and Fig 4A, lane 3). The activity was increased slightly after reperfusion and attenuated almost to the basal level at 60 minutes (Fig 4A, lanes 4 to 6). However, after 20 or 40 minutes of ischemia, reperfusion induced a burst of the activation, and the activity continued for >60 minutes (Fig 4A, lanes 7 to 14; and Fig 4B). The HSE-binding activity was observed similarly for 
180 minutes during reperfusion after 20-minute ischemia (data not shown). Thus, postischemic reperfusion caused a significant induction of HSE-binding activity of HSF. Longer ischemic treatment before reperfusion caused more-prolonged HSF activation during reperfusion. In any time point, the HSE-binding activity was significantly weaker compared with that in heat-shocked hearts. Binding activity to the labeled HSE in an extract of hearts, which were treated with 20-minute ischemia and 10-minute reperfusion, was competed out by an excess of unlabeled HSE oligonucleotides (Fig 4C, lanes 4 and 5). In contrast, a 100-fold excess of unlabeled CREB and NF-B oligonucleotides failed to compete at all (lanes 7 and 8). Competition experiments with extracts from hearts subjected to heat shock or ischemia without reperfusion yielded the same results (data not shown). These demonstrated the specificity of the HSE/HSF interaction in heat-shocked and ischemia-reperfused hearts.
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Specific Activation of HSF1
It has been shown that HSF1 is activated during heat shock in cultured cells, rat brain, and murine tissues, including the heart.7 8 28 38 To find out which HSF is responsible for the activity induced by ischemia/reperfusion, we used antisera against HSF1 and HSF2 to retard the electrophoretic mobility of HSF/HSE complexes. In extracts representing both 40-minute heat shock and 20-minute ischemia followed by 10-minute reperfusion, supershifts or decreases in mobility of the complex were observed when antiserum against HSF1 was used (Fig 5, lanes 2, 3, 8, and 9), although anti-HSF2 antiserum had no effect (lanes 5, 6, 11, and 12). Similar experiments were performed for other time points or ischemia without reperfusion and yielded the same results (data not shown). These results demonstrate that HSF1 is the primary component of HSE-binding activity induced by ischemia or reperfusion as well as by heat shock in hearts.
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The protein level of HSF1 in tissues was analyzed by Western blot using anti-HSF1 antibody (data not shown). The amount of HSF1 in the heart was lower than that in the adrenal gland or testis but higher than that in the liver, kidney, brain, or skeletal muscle, as reported in the mouse.38
Induction of mRNAs for HSPs
To determine whether the HSF activation during heat shock or ischemia/reperfusion resulted in the subsequent transcription of HSPs, we examined the levels of mRNA for HSP70, HSP90, and GRP78 by Northern blot analysis (Fig 6). The HSP70 probe hybridized with three distinct transcripts.28 Two larger transcripts, which are 2.8 and 3.1 kb, corresponding to inducible HSP70 mRNA species, were hardly detected in control hearts (Fig 6A, lanes 1 and 2) but were clearly induced after heat shock (lanes 3 to 7) or postischemic reperfusion (see below). In the heart after ischemia for 10 to 60 minutes without reperfusion, a faint level of expression was detected (lanes 8, 11, and 16). The relative radioactivity of each band was counted, normalized by ß-actin, and compared with the band in control hearts (30 minutes) as shown in Fig 6B and 6C. The level of HSP70 mRNA expression during heat shock increased up to 180 minutes and reached 120-fold higher than the control level. HSP70 mRNA expression in hearts during reperfusion after 20-minute ischemia reached a peak at 120 minutes and was 80-fold higher than that of control heart. HSP90 mRNA during heat shock gradually increased up to 180 minutes, but the level of its accumulation was only approximately fivefold greater than the control value. On the other hand, HSP90 mRNA was strongly induced in hearts subjected to 20-minute ischemia and the following reperfusion. The maximal level of its expression at 120-minute reperfusion was 17-fold higher than that of control hearts. Thus, the expression of HSP70 mRNA during heat shock was stronger than that during postischemic reperfusion, whereas the HSP90 mRNA expression was significantly stronger in reperfused hearts after 20-minute ischemia than in heat-shocked hearts.
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The level of GRP78 mRNA was not significantly changed during heat shock or ischemia/reperfusion compared with that of control heart (data not shown).
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Discussion |
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In this study, we demonstrated that the reperfusion causes significant response of heat shock genes in the ischemic rat heart. Several studies have been conducted of induction of the stress response in hearts through the investigation of mRNA or protein. However, accumulation of these substances takes a long time. Because the induction of HSE-binding activity of HSF is observed immediately after the onset of the stimulus, as we observed in the heat-shocked or ischemic heart, gel mobility shift assay is thought to be a more appropriate method for exploring the types of stimulus inducing the stress response. With this assay, we demonstrated that the induction of HSE-binding activity of HSF during ischemia was weak and the activity soon attenuated and that postischemic reperfusion induced a significant activation of HSF. In addition, although HSP70 mRNA was hardly induced even after 60-minute ischemia, its burst induction was detected after 20- or 60-minute reperfusion. These results apparently indicate that reperfusion is the main stimulus for stress response in the ischemia-reperfused heart.
In the liver and kidney, it was shown that ischemia induced definite HSF activation and that ischemia/reperfusion enhanced the activation.39 40 The relative activity of HSF during ischemia in our study was much weaker than that shown in the liver or kidney. This difference may be due to tissue specificity and the types of experimental models. The perfusion of the isolated heart was completely cut off by clamping of the aortic cannula, whereas collateral or residual perfusion may have affected the activity in these ischemic models in the liver and kidney. It was reported that HSP70 mRNA was induced by low-flow perfusion rather than by little or no perfusion.41 The systematic investigation in our present study revealed that compared with ischemia alone, postischemic reperfusion induces a higher level of HSE-binding activity of HSF.
In this study, we also demonstrated that ischemia/reperfusion as well as heat shock induces the activation of HSF1 in the heart and that HSF1 regulates heat shock gene transcription, as has been reported in cultured cells, tissues in heat shock, or ischemic brain.7 8 28 38 These results suggest that the same regulatory pathway of heat shock gene transcription that is activated in heat-shocked cells becomes activated systemically in whole animals under ischemic or other stresses.
Another point of interest is the nature of the primary signal that activates HSF1 during ischemia/reperfusion. Recent studies are consistent with the following model for regulation of heat shock response in which the HSPs themselves negatively regulate the heat shock gene expression by way of an autoregulatory loop.36 42 43 44 Under a nonstressful condition, HSF1 is maintained in a monomeric form through transient interactions with HSP70. During heat shock or other stresses, the accumulation of misfolded or aggregated proteins causes the mobilization of HSP70, resulting in the depletion of the free pool of HSP70; consequently, negative regulatory influence on HSF activation is removed. The released HSF assembles into trimers, acquires DNA binding activity, and leads to the elevated rate of synthesis of HSPs. During ischemia/reperfusion, multiple and complex pathological changes occur in the heart. These changes include accumulation of intracellular Ca2+, loss of high-energy phosphate esters, membrane damage, mitochondrial failure, altered osmotic control, decreased intracellular pH, and the subsequent production of oxygen free radicals involving the arachidonic acid metabolic pathway.26 A decrease in intracellular ATP was reported to activate HSF and result in HSP70 induction.40 45 However, as the present study revealed, although HSF activation was very weak during global heart ischemia, in which ATP was reported to be depleted rapidly,46 prompt and significant activation was induced by postischemic reperfusion, in which the ATP level gradually increases. Iwaki et al47 demonstrated that the induction of HSP70 mRNA preceded the intracellular ATP depletion caused by hypoxia in cardiomyocytes. These findings suggested that ATP depletion is not the main stimulus for stress response in the ischemia-reperfused heart. Oxidative stress, which has been considered to be the main cause of reperfusion injury, was demonstrated not to induce the expression of HSP70 mRNA despite HSF activation.39 48 Although reduction of pH to nonphysiological levels (<6.2) was reported to activate HSF,49 severe acidosis (pH 6.7) in the physiological range did not induce HSF-binding activity in intact cells.45 Recent studies have revealed that antiproliferative prostaglandins or arachidonic acid also activates HSF.50 51 These findings suggest a relation between arachidonic acid metabolism and the stress response under pathological conditions. Although the detailed mechanisms remain to be elucidated, it seems likely that ischemia/reperfusion disturbs protein metabolism, generates misfolded proteins, and activates HSF1.
Our study showed that the activity of HSF1 and the expression of HSP70 mRNA during heat shock were greater than those during postischemic reperfusion. In contrast, HSP90 mRNA was significantly more strongly induced during reperfusion after 20-minute ischemia than during heat shock. Even though all heat shock genes may have similar promoter regions, there was a striking contrast in the heart between HSP70 and HSP90 concerning the relative accumulation of mRNA in response to heat shock or ischemia/reperfusion. Differential regulations of HSP70 and HSP90 are also reported in lymphocytes or peripheral blood monocytes.52 53 In these cells treated by phorbol esters, HSP90 are preferentially induced compared with HSP70. These findings suggest the involvement of additional regulatory mechanisms, such as undefined elements in the promoter regions or differences in mRNA stability, in addition to the transcriptional regulation via an HSE sequence.
The myocardial protective effect of HSPs has been demonstrated.18 19 20 21 22 23 24 25 Further research on the mechanisms of HSP induction in the heart and more-intensive study of less-noxious stimuli that induce HSPs effectively are necessary. We believe that these explorations can result in valuable clinical applications relevant to cardiac surgery or treatments for ischemic heart disease.
In summary, the present study indicates that reperfusion causes a significant activation of HSF in the ischemia-reperfused heart and that HSF1 was the primary component of HSE-binding activity induced by ischemia or reperfusion as well as heat shock in the heart. Although the expression of HSP70 mRNA during heat shock was greater than the expression during ischemia/reperfusion, HSP90 mRNA was significantly more strongly induced in ischemia/reperfusion than in heat shock. This result suggests that individual HSPs are regulated by additional mechanisms other than HSF. We believe that further research on the mechanisms of induction of stress proteins will result in valuable clinical application.
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Acknowledgments |
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This study was supported in part by a grant-in-aid from the Ministry of Education, Science and Culture of Japan. We gratefully thank Dr Masaki Aota for technical advice.
Received January 31, 1996; revision received May 5, 1996; accepted May 15, 1996.
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