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Cardiovascular Research 1999 43(4):939-946; doi:10.1016/S0008-6363(99)00185-6
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Copyright © 1999, European Society of Cardiology

Heat stress fails to protect myocardium of streptozotocin-induced diabetic rats against infarction

Marie Joyeuxa, Patrice Faureb, Diane Godin-Ribuota, Serge Halimib, Asha Patelc, Derek M Yellonc, Pierre Demengea and Christophe Ribuota,*

aLaboratoire de Pharmacologie Cardiovasculaire Expérimentale-Biomolécules, Université Joseph Fourier, U.F.R. de Pharmacie, Grenoble, France
bLaboratoire de Biologie du Stress Oxydant, Université Joseph Fourier, U.F.R. de Pharmacie, Grenoble, France
cThe Hatter Institute for Cardiovascular Studies, University College London Hospitals & Medical School, London, UK

* Corresponding author. Corresponding address: Laboratoire de Pharmacologie, Faculté de Pharmacie, Domaine de la Merci, 38706 La Tronche Cedex, France. Tel.: +33-476-637-108; fax: +33-476-637-152 Christophe.Ribuot{at}ujf-grenoble.fr

Received 18 February 1999; accepted 14 April 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Material and methods
 3 Results
 4 Discussion
 References
 
Objective: Protection conferred by heat stress (HS) against ischaemia–reperfusion injury, in term of mechanical function and myocardial necrosis, has been extensively studied. In contrast, the effects of disease states on this HS-induced cytoprotective response are less known. Therefore, we investigated the effects of prior heat stress on the infarct size in the isolated heart and on the myocardial heat stress protein (HSP) 72 synthesis, in a model of insulin-dependent diabetic rats. Methods: Three groups of animals were studied: D rats were rendered diabetic by 55 mg/kg streptozotocin i.v. injection, DI rats received the same treatment plus a daily injection of insulin started 2 weeks after and V rats received the vehicle of streptozotocin plus a daily injection of saline. Eight weeks later, D, DI and V rats were either heat-stressed (42°C for 15 min) or sham-anaesthetised. Twenty-four hours later, their hearts were isolated, perfused using the Langendorff technique, and subjected to a 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. Myocardial HSP72 content was measured 24 h after HS or sham treatment using an electrophoresis coupled with a Western blot analysis. Results: Infarct-to-risk ratio (I/R) was significantly reduced in hearts from heat-stressed (11.7±2.0%) compared to sham (30.0±3.2%) V rats. This cardioprotection was not observed in hearts from D (I/R: 31.4±3.3 vs. 34.3±3.5%) and DI (I/R: 28.7±1.6 vs. 30.3±1.6%) rats. Risk zones were similar between all experimental groups. The incidence of ventricular arrhythmias during ischaemia and reperfusion periods was not different between the six experimental groups. Western blot analysis of the myocardial HSP72 content showed a comparable heat stress-induced increase of this protein, in V, D and DI animals. Conclusion: These results demonstrate that myocardial protective effect induced by heat stress could not extend to a pathological animal model like the diabetic rat and seems to be unrelated to the HSP72 level. Further investigations are required to elucidate the precise role of the heat stress proteins in this adaptive response.

KEYWORDS Heat stress; Infarct size; Diabetic rats; Streptozotocin; Heat stress protein


   1 Introduction
Top
 Abstract
 1 Introduction
2 Material and methods
 3 Results
 4 Discussion
 References
 
Heat stress (HS), as well as other environmental stresses, is known to induce synthesis of heat stress proteins (HSP) which play an important role in the cell’s ability to survive noxious stresses [1,2]. In particular, the myocardial induction of HSP72, occurring 24 h following whole body hyperthermia, is associated with protection against ischaemia–reperfusion injury [3–6] and has been correlated to the degree of HS-induced ischaemic tolerance [7,8].

Although the cytoprotective response induced by heat stress is reasonably well known in non-pathological animals, our knowledge of the effects of disease states on this HS-induced cardioprotection is limited. Since cardiac events are usually associated with underlying cardiovascular diseases, it is important to study the development of the stress response in animal models of diabetes, a disease associated with endothelial [9] and myocardial [10,11] dysfunctions. As a matter of fact, an altered sensitivity to ischaemic injury has been observed in various models of diabetes [12,13].

Furthermore, the cardioprotection, induced 24 to 48 h following heat shock, resembles that observed during the second window of protection following ischaemic preconditioning [14–16]. When investigated in diabetic animals, ischaemic preconditioning has been reported to reduce infarct size in a non-insulin-dependent diabetic rat model in vivo [17]. Moreover, this preconditioning can protect endothelial function in resistance coronary arteries of diabetic hearts [18]. On the other hand, Tosaki and co-workers [19,20] have demonstrated that ischaemic preconditioning failed to reduce the incidence of ventricular arrhythmias and to improve myocardial function of diabetic rat hearts.

Therefore, we investigated in this study whether heat stress can afford protection against myocardial infarction after an ischaemia–reperfusion sequence, in streptozotocin-induced diabetic rats, treated or not with insulin, and their age-matched controls. The heat stress-induction of cardiac HSP72 synthesis was also assessed in these animals.


   2 Material and methods
Top
 Abstract
 1 Introduction
 2 Material and methods
3 Results
 4 Discussion
 References
 
2.1 Experimental groups
The care and use of animals in this work were in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). Male Wistar rats, weighing 240–270 g, were used. Diabetes was induced by a single injection of 55 mg/kg streptozotocin (STZ, Sigma, France) [18] via the penian vein of rats anaesthetised with pentobarbital (D group). Diabetes was confirmed by the presence of glycosuria and polydypsia, detected 2 weeks after the STZ injection. Half of the diabetic rats (DI group), randomly chosen, were daily subcutaneously injected with 4 IU of insulin (Lente MC, Novo, France) in the afternoon [21], 2 weeks after the STZ injection. Age-matched control anaesthetised rats (V group) were injected with the vehicle of the STZ (0.1 M citrate buffer, pH 4.5). D and V groups were daily subcutaneously injected with saline, 2 weeks after they received STZ or vehicle, respectively.

After 8 weeks, D, DI and V rats were submitted to either heat stress (HS) or anaesthesia without hyperthermia (sham). All animals were allowed to recover for 24 h before their heart was isolated, perfused in the Langendorff mode and submitted to an ischaemia (30 min)–reperfusion (120 min) sequence.

Six experimental groups were studied: Group Sham-D (n=6) – diabetic rats submitted to sham anaesthesia; Group Sham-DI (n=6) – insulin-treated diabetic rats submitted to sham anaesthesia; Group Sham-V (n=6) – control rats submitted to sham anaesthesia. In groups HS-D (n=6), HS-DI (n=6) and HS-V (n=6), rats were similarly treated prior to undergoing heat stress. The experimental protocol is summarised in Fig. 1.


Figure 1
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  		Fig. 1 Experimental protocol.

 
2.2 Heat stress protocol
Whole body hyperthermia was achieved as previously described [22], by placing anaesthetised (with 25 mg/kg, i.p. sodium pentobarbitone) D, DI or V animals in an environmental chamber under an infra-red light. Their body temperature, recorded with a rectal probe, was increased to 42±0.2°C for 15 min. Sham animals were anaesthetised only. Rats were heat-stressed or sham-anaesthetised in the morning, they received insulin or saline injection in the afternoon (as the day before) and were submitted to the ischaemia–reperfusion protocol the following morning.

2.3 Ischaemia–reperfusion protocol
Twenty-four hours after heat stress, the rats received heparine (1000 U/kg, i.p.) and were anaesthetised with sodium pentobarbitone (60 mg/kg, i.p.). Blood glucose concentration was then measured using an Accu-Chek Glucose Monitor (Boehringer Mannheim). The heart was rapidly excised and immediately immersed in 4°C Krebs–Henseleit buffer solution (NaCl 118.0, KCl 4.7, CaCl2 1.8, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25.2 and glucose 11.0 mM). The aortic stump was then cannulated and the heart perfused using the Langendorff technique at a constant pressure (75 mm Hg) with oxygenated Krebs–Henseleit buffer. A water-filled latex balloon, coupled to a pressure transducer (Statham) was inserted into the left ventricular cavity via the left atrium for pressure recordings. Left ventricular end-diastolic pressure (LVEDP) was adjusted between 8–12 mm Hg. Myocardial temperature was measured by a thermoprobe inserted into the left ventricle and was maintained constant close to 37°C. For temporary occlusion of the left coronary artery (LCA), a 3/0 silk suture (Mersilk W546, Ethicon) was placed around the artery a few millimeters distal to the aortic root. After 20 min of stabilization, regional ischaemia was induced by tightening the snare around the LCA for 30 min [23]. Thereafter the heart was reperfused for 120 min. Coronary flow (CF) was measured throughout the ischaemia–reperfusion procedure, by collecting the effluent. Heart rate (HR) and left ventricular developed pressure (LVDP=difference between left ventricular systolic pressure and LVEDP) were continuously recorded on a polygraph (Windograph, Gould Instrument). At the end of the reperfusion period, the coronary artery ligature was retied and unisperse blue dye (Ciba–Geigy, France) was slowly infused through the aorta to delineate the myocardial risk zone. After removal of the right ventricle and connective tissues, the heart was frozen and then cut into 2 mm transverse sections from apex to base (six to seven slices/heart). Once defrosted, the slices were incubated at 37°C with 1% triphenyltetrazolium chloride (Sigma, France) in phosphate buffer (pH 7.4) for 10–20 min and fixed in 10% formaldehyde solution to distinguish clearly stained viable tissue and unstained necrotic tissue. Left ventricular infarct zone (I) was determined using a computerised planimetric technique (Minichromax; Biolab) and expressed as the percentage of the risk zone (R) and of the left ventricle (LV).

2.4 Quantification of arrhythmias
Arrhythmias were classified in accordance with the Lambeth Conventions guidelines [24]. Electrogram recordings were analysed for the incidence (%) of ventricular tachycardia and/or fibrillation (VT–VF) occurring during ischaemia and reperfusion.

2.5 Determination of myocardial HSP72 content
For myocardial HSP72 content determination, additional animals (n=2 or 3 per group) were submitted only to HS or sham anaesthesia. Twenty-four hours later, D, DI or V rats were anaesthetised (60 mg/kg sodium pentobarbitone, i.p.), heparinised (1000 U/kg, i.p.) and their heart was quickly excised as described in Section 2.3. Left ventricular tissue samples (50 mg) were rapidly powdered in liquid nitrogen and suspended in 500 µl SDS–PAGE sample buffer (20% glycerol, 6% sodium dodecyl sulphate, 1.4% Tris–HCl, pH 6.8). 2-Mercaptoethanol (10%) was added and the samples were heated at 100°C for 10 min. Samples were cooled and centrifuged at 11 000 g for 5 min. Bromophenol blue (8%) was added to the supernatant and the samples were stored at –20°C. Proteins were separated by electrophoresis on 12.5% polyacrylamide SDS–PAGE gels. Gels were stained in Coomassie blue R250 and subsequently destained to confirm equivalence of protein loading. For Western blot analysis of HSP72, proteins were transferred electrophoretically onto nitrocellulose membrane (Hybond-C, Amersham, UK) overnight at 180 mA and 4°C. The membrane was placed in washing buffer for 30 min (phosphate buffered saline, pH 7.2, containing 0.05% Tween 20 and 0.1% dried milk powder) to block non-specific binding sites. The filter was first incubated (60 min) with a mouse monoclonal IgG cross-active to HSP72 (SPA-810, StressGen) at 1:1000 dilution and subsequently incubated (60 min) with horseradish peroxidase-conjugated rabbit anti-mouse IgG (P260, Dako, Denmark) at 1:2500 dilution. The filter was developed using an enhanced chemiluminescence detection system (Amersham).

2.6 Statistical analysis
Arrhythmia incidences were compared using exact Fisher’s tests. The other data are presented as mean±SEM. Comparisons of CF, HR and LVDP were determined by repeated measures ANOVA. Hyperglycaemia, body weight, heart weight and infarct size were analysed by one-way ANOVA with post-hoc multiple comparison Tukey tests. p values ≤0.05 were considered significant.

2.7 Exclusion criteria
Only hearts with CF within 8–15 ml/min and LVDP >70 mm Hg at the end of the stabilization period were included in this study. The efficiency of coronary occlusion was indicated by a decrease in CF >30%. Hearts which developed ventricular fibrillation (VF) during ischaemia–reperfusion that could not be restored to normal sinus rhythm within 2 min were excluded [23].


   3 Results
Top
 Abstract
 1 Introduction
 2 Material and methods
 3 Results
4 Discussion
 References
 
3.1 Glycaemia, body weight and heart weight in D, DI and V rats
Table 1 presents glycaemia, body weight and heart weight values assessed in V, D and DI animals. In STZ-treated rats, glycaemia was significantly higher than in age-matched V rats whereas body weight was significantly lower. In DI animals, 6 weeks of daily injection of insulin rendered the glycaemia and the body weight comparable to those of V rats.


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  		Table 1 Glycaemia, body weight and heart weight assessed in V (vehicle-treated), D (STZ-treated) and DI (STZ plus insulin-treated) rats, 8 weeks after the treatmenta

 
3.2 Haemodynamic data
Table 2 summarises CF, HR and LVDP data recorded in the six experimental groups during the stabilization and the ischaemia–reperfusion. Twenty-four hours after heat stress or sham anaesthesia, a significant bradycardia was observed in diabetic hearts throughout the study. In DI animals, the heart rate was not different with that of V rats. The other haemodynamic parameters did not differ between the six experimental groups.


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  		Table 2 Haemodynamic data, n=6 in each groupa,b

 
3.3 Arrhythmias data
The incidence of ventricular arrhythmias during ischaemia and reperfusion periods is presented in Table 3. Twenty-four hours after heat stress or sham anaesthesia, there was no statistically significant difference in VT–VF incidence between the six experimental groups.


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  		Table 3 Incidence (%) of ventricular tachycardia and or fibrillations (VT–VF) during the ischaemia and the 120 min reperfusion periodsa,b

 
3.4 Infarct size data
Table 4 summarises infarct size data expressed as the percentage of the risk zone (I/R) and of the left ventricle (I/LV) for the six experimental groups. Heat stress induced a 61% decrease of I/R in hearts from V animals whereas no protection was seen in D and DI hearts (p≤0.001 by one-way ANOVA, Fig. 2). Similar results were observed concerning the I/LV ratio (Table 4). Myocardial risk size expressed as the percentage of the left ventricle (R/LV) was similar for all groups (Table 4). Differences in infarct size, therefore, did not result from variability in the risk zone.


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  		Table 4 Risk (R) and Infarct (I) sizes expressed as a percentage of the left ventricle (LV)a,b

 

Figure 2
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  		Fig. 2 Infarct size (I) expressed as a percentage of the risk zone (R) in isolated rat hearts subjected to a 30 min coronary occlusion followed by 120 min of reperfusion, from Sham-V (vehicle-treated sham-anaesthetised rats), HS-V (vehicle-treated heat-stressed rats), Sham-D (STZ-treated sham-anaesthetised rats), HS-D (STZ-treated heat-stressed rats), Sham-DI (STZ plus insulin-treated sham-anaesthetised rats), HS-DI (STZ plus insulin-treated heat-stressed rats) groups. * p≤0.001.

 
3.5 HSP72 analysis
Western blot analysis of myocardial HSP72 content of the six experimental groups is presented in Fig. 3. In V animals, a marked increase in this protein was observed following heat stress (HS-V vs. Sham-V groups). This confirms the adequacy of the heat stress protocol. This heat stress-increase in HSP72 was also seen in the myocardium of D (HS-D vs. Sham-D groups) and DI (HS-DI vs. Sham-DI groups) rats.


Figure 3
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  		Fig. 3 Western blot analysis of myocardial HSP72 (72 kD) content in groups Sham-V (vehicle-treated sham-anaesthetised rats), HS-V (vehicle-treated heat-stressed rats), Sham-D (STZ-treated sham-anaesthetised rats), HS-D (STZ-treated heat-stressed rats), Sham-DI (STZ plus insulin-treated sham-anaesthetised rats), HS-DI (STZ plus insulin-treated heat-stressed rats). n=2 or 3 per group.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Material and methods
 3 Results
 4 Discussion
References
 
In this study, we observed in non-diabetic rats that heat stress led to a delayed cardioprotection by significantly reducing infarct size in the isolated heart subjected to an ischaemia–reperfusion sequence, in accordance with previous in vivo [4,6] and in vitro [23,25] studies. We demonstrated that this delayed resistance to myocardial infarction cannot be reproduced in a pathological rat model of insulin-dependent diabetes mellitus, even though the animals were treated with insulin. Moreover, myocardial HSP72 synthesis was enhanced by heat stress in both non-diabetic and diabetic animals.

Diabetes mellitus is often associated with cardiovascular complications, such as coronary artery disease and diabetic cardiomyopathy, resulting in an increased risk of myocardial infarction and congestive heart failure [13,26]. Moreover, the presence of diabetes dramatically reduces survival after myocardial infarction even though the size of the infarct is not significantly different compared to the non-diabetic population [12,13,27]. Hence, experimental therapies that protect healthy myocardium will be more clinically relevant if they also protect the diabetic heart.

While clinical studies have demonstrated that diabetic hearts are more susceptible to ischaemic injury, studies using experimental models of chemically-induced diabetes have reported increased, decreased or unchanged sensitivities to ischaemia [12,13]. A possible explanation for this controversy could be a difference in the duration and the severity of the diabetic state studied as well as in the ischaemia–reperfusion protocol used. Thus, it seems that following 2–3 weeks of diabetes (induced by a ‘classical’ dose of STZ) hearts develop resistance to ischaemia whereas they became identically or more sensitive than the non-diabetic hearts following six and more weeks of diabetes [20,26,28]. In accordance with other studies using the same dose of STZ and the same duration of diabetes [18,28,29], we have shown a comparable sensitivity to ischaemia in diabetic and non-diabetic hearts since the incidence of ventricular arrhythmias and the infarct size did not differ.

In our isolated cardiac preparations, we observed that STZ-induced diabetes is associated with a bradycardia which is normalised by an insulin treatment, in accordance with other studies [30,31]. This depression in basal spontaneous pacemaker rate may result from changes in electrophysiological properties of sino-atrial node [30].

Among the experimental therapies that protect both healthy and diabetic myocardium against ischaemic injury, adenosine-pretreatment or ischaemic preconditioning are known [17,18,32]. However, Bouchard and Lamontagne [18] have shown that preconditioning must be more extensive and adenosine perfusion period be longer in diabetic compared with non-diabetic hearts to achieve the same degree of endothelial protection. That possibly explains why Tosaki and his team [19,20] observed that ischaemic preconditioning fails to protect diabetic rat hearts against ischaemia. In this study, we have investigated the potential cardioprotection of another experimental therapy, the heat stress. Few studies have explored the myocardial protection induced by heat stress in pathological models [33,34]. We have previously demonstrated that heat stress was able to protect hypertrophied myocardium from transgenic ((mREN-2)27) hypertensive rats against infarction [34]. Here, we show that this heat stress-induced protection is not seen in diabetic hearts, even though the animals were treated with insulin. It is difficult to compare the protection induced by ischaemic preconditioning and heat stress, since the end-point used in the studies [18,19] was different. Furthermore, some could argue diabetic hearts might require a more extensive heat exposure to be protected. Unfortunately, this hypothesis is hard to verify because of the high lethality induced by a prolonged hyperthermia. Alternatively, it cannot be excluded that the window of protection might also be altered by diabetes and further investigations are needed to explore this point.

Among the variety of myocardial abnormalities induced by diabetes, increased protein kinase C activity has been reported [35], resulting in depressed Na+–Ca2+ exchanger activity [36]. It has also been shown that ATP-sensitive potassium (KATP) channels are altered in ventricular myocytes from diabetic rats [37,38]. Since activation of protein kinase C (PKC) and opening of KATP channels appear to be crucial intermediate steps in the resistance to myocardial infarction induced by heat stress [25,39], as well as by ischaemic preconditioning [40], it could be of interest to explore if their alteration may explain the loss of protection following these preconditionings. Other abnormalities exhibited by diabetic myocardium, such as depressed Na+–H+ activity [41], decreased sarcoplasmic reticular Ca2+ pump activity [42] and altered antioxidant defences [43], may influence ischaemic injury and could also be implicated.

Another purpose of this study was to evaluate myocardial HSP72 expression following hyperthermia, in non-diabetic and diabetic rats, treated or not with insulin. In the absence of heat stress, our results show that there is a comparable small basal synthesis of this protein in hearts from V, D and DI rats, suggesting that neither streptozotocin nor insulin treatments affect the myocardial HSP72 expression. Twenty-four hours following heat stress, myocardial HSP72 expression was identically enhanced in V, D and DI groups whereas only the V group was protected against infarction.

Several studies point to a relationship between HSP72 induction and cardioprotection. Hence, Marber and co-workers [6] have observed that prior hyperthermia induces a high level of myocardial HSP72 expression along with the enhanced myocardial tolerance to ischaemic injury. Furthermore, the level of HSP72 has been correlated to the degree of heat stress-induced cardioprotection in the rat [7] and in the rabbit [8]. Finally, improved functional recovery has been observed in isolated perfused transgenic mice [44,45] and rat [46] hearts overexpressing HSP72 and subjected to an ischaemia–reperfusion sequence. However, we have previously shown that infarct size reducing effect conferred by heat stress was abolished by both {alpha}1-adrenoceptor blockers [23] and PKC inhibitor [25] without changes in HSP72 induction, suggesting that other potential cytoprotective mechanisms or end-effectors could be implicated in this response. Since many crucial intermediate steps (as PKC, KATP channels, antioxidant defences, sarcoplasmic reticular Ca2+ pump [2]) of the heat stress-induced cytoprotection are altered in the diabetic myocardium, it is not surprising that this protection was abolished in the diabetic heart although HSP72 synthesis was enhanced. On the other hand, altered gene regulation of another heat stress protein, the heme oxygenase-1 (also named HSP32) has been reported in cardiac tissues of STZ-induced diabetic rats [47]. Further investigations are required to clarify the signal transduction pathways which co-ordinate the heat stress response and the potential role of the different HSP in both non-diabetic and diabetic hearts.

In summary, this study provides the first observation that heat stress fails to protect the isolated heart of diabetic rats against ischaemia–reperfusion injury even though the animals were treated with insulin. Finally, while heat stress induces high levels of HSP72 in diabetic hearts, the synthesis of these proteins appears not to be sufficient to protect the diabetic heart, suggesting that presently unidentified mechanisms associated with streptozotocin-induced diabetes prevent the acquisition of protection against ischaemia–reperfusion injury after heat stress.

Time for primary review 21 days.


   References
Top
 Abstract
 1 Introduction
 2 Material and methods
 3 Results
 4 Discussion
 References
 

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