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Annals of Clinical & Laboratory Science 35:161-168 (2005)
© 2005 Association of Clinical Scientists

Recombinant Human Erythropoietin Pretreatment Attenuates Myocardial Infarct Size: A Possible Mechanism Involves Heat Shock Protein 70 and Attenuation of Nuclear Factor-kappaB

Biao Xu1, Guo-hua Dong1, Hong Liu1, Yan-qing Wang2, Hai-wei Wu1 and Hua Jing1
1 Department of Cardiothoracic Surgery and 2 Department of Cardiology, Jingling Hospital, Nanjing University Medical School, Nanjing, People’s Republic of China

Address correspondence to Biao Xu, M.D., Department of Cardiovascular Surgery, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, People’s Republic of China; tel 86 25 8481 9984; fax 86 25 8480 6839; e-mail xubiao3000{at}msn.com.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Discussion
 Acknowledgement
 References
 
Erythropoietin (EPO), known for its role in stimulating erythropoiesis, has recently been shown to have a cardio-protective effect in animal models of myocardial ischemia-reperfusion (I-R) injury. The mechanism of the cardio-protective effect of EPO is unclear. Part of the mechanism for EPO-induced cardio-protection may involve inhibition of myocardial apoptosis and preservation of ATP levels in the ischemic myocardium. We studied the expression of heat shock protein 70 (Hsp70) and its possible links to the cardio-protective effect of EPO. A rat model of myocardial I-R injury was established by ligating the left descending coronary artery for 30 min and then reperfusing for 2 hr. Recombinant human EPO (rhEPO) was injected ip 24 hr before the ligation. The myocardial infarct size and the area at risk of ischemia were measured by staining with triphenyltetrazolium chloride (TTC) and Evans blue dye. Expression of Hsp70 in the left ventricle was analyzed by ELISA and that of nuclear factor-kappaB (NF-{kappa}B) was analyzed by electrophoretic mobility shift assay (EMSA). The results showed that a single ip injection of 3,000 units/kg of rhEPO at 24 hr pre-ligation enhanced the expression of Hsp70 and diminished the expression of NF-{kappa}B in rat myocardium, and that the myocardial infarct induced by I-R injury was remarkably reduced in size, compared to control rats that received an ip saline injection at 24 hr pre-ligation.

(received 10 November 2004; accepted 22 December 2004)

Keywords: apoptosis, erythropoietin, Hsp70, NF-{kappa}B, ischemia-reperfusion injury, myocardial infarction


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Discussion
 Acknowledgement
 References
 
Erythropoietin (EPO) has been viewed as a hemato-poietic cytokine produced by the fetal liver and adult kidney in response to hypoxia. Recent work has extended the classical role of EPO from a mediator of erythroid maturation to one that protects against ischemia-reperfusion (I-R) injury in various tissues, including brain [1,2], retina [3], vascular smooth muscle [4], endothelial cells [5], and heart [7,8].

Several studies have explored the underlying mechanism of EPO protection. The effect of EPO during I-R injury involves an ability to modulate local responses to injury by attenuating both inflammatory and apoptotic causes of cell death [8]. Another way that EPO may affect the inflammatory response is by modulating members of the NF-{kappa}B family, principal regulators of inflammatory genes [9,10]. Inhibition of NF-{kappa}B in experimental I-R injury has been demonstrated using pretreatment with decoy oligonucleotides, proteasome inhibitors, and lipopolysaccharide (LPS) [11]. Shimizu et al [12] found that LPS pretreatment induced Hsp70 expression in myocardium, which inhibited NF-{kappa}B activation, and reduced infarct size after I-R in rats [12]. Recently, researchers found that the protective effect of rhEPO is associated with induction of members of the heat shock protein (Hsp) family, including Hsp70 and Hsp27 [13,14]. The present study evaluated whether or not the cardio-protective effects of rhEPO are related to induction of Hsp70 and/or attenuation of the expression of NF-{kappa}B.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Discussion
 Acknowledgement
 References
 
Animals, drugs, and experimental design.  Adult male Sprague-Dawley rats, weighing 400 ± 10 g, were obtained from the Chinese Academy of Science Nanjing University Animal Centre. All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society of Medical Research and the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (Publication No. 85-23, revised 1996). The experimental protocol was approved by the Nanjing University Animal Care and Use Committee. The rats were housed and fed at the Animal Center of Jinling Hospital at least 7 days before surgery in order to accustom them to the environment.

The rhEPO was purchased from Shenyang Sunshine Pharmaceutical Co (Shenyang, China).

The experimental design is shown in Fig. 1.Go Three experimental groups were studied: a sham operation group (ip saline solution, 2 ml; n = 6); a control group (ip saline solution, 2 ml, n = 18); and an rhEPO group (ip rhEPO, 3,000 units/kg body wt (bw), diluted in 2 ml of saline solution, n = 18).



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  		Fig. 1. Experimental design. There were 3 groups of rats: the sham operation group, the control group, and the rhEPO group. "Hsp70" indicates the time of sampling for measurements of Hsp70 protein in myocardial cytosol (n = 6 in each group). "NF- {kappa}B" indicates the time of sampling to evaluate NF-{kappa}B activation in nuclear protein extracts (n = 6 in each group). "Infarct size" indicates the time for preparation of myocardial tissue for measurements of infarct size (n = 6 in each group).

 
Surgical procedures.  To induce myocardial I-R injury, the rats were anesthetized by ip injection of sodium pentobarbital, 50 mg/kg bw. A cannula was inserted into the trachea and the rats were ventilated with room air using a positive pressure respirator (Rodent Respirator, TKR-200C, China). Body temperature was maintained at 36–37°C by a heating lamp placed above the animal. Peripheral limb electrodes were inserted sc and an electrocardiogram (ECG) was continuously recorded for the duration of the experiment. Arterial pressure was monitored by placing a catheter in the right femoral artery.

A left thoracotomy was performed via the fourth intercostal space to expose the heart. The main left coronary artery (LCA) was ligated with a 6-0 silk suture placed 2 to 3 mm proximal to the origin of the first diagonal branch.

Successful ligation was indicated by elevation of the ST segment on the ECG and by cyanosis of the anterior wall of the left ventricle. Hearts of rats in the control and rhEPO-treated groups were subjected to 30 min of ischemia followed by 2 hr of reperfusion (removal of the ligature).

The sham-operated control group was subjected to thoracotomy and passage of a silk ligature around the LCA without ligation. All subsequent procedures were performed under aseptic conditions.

Determination of area at risk and infarct size.  Two hr after post-ischemic reperfusion, the left anterior descending coronary artery was re-ligated with a loose silk suture in the same location as the previous ligature and 3 ml of 2% Evans blue dye (Fluka, Switzerland) was injected via the right jugular vein to delineate the area at risk (AAR). When the epicardial surface turned blue, the heart was harvested and frozen at –20°C for 30 min, and cut into 5 or 6 transverse slices (2-mm thick), which were incubated for 10 min at 37°C in a 1% solution of 2,3,5- triphenyltetrazolium chloride (TTC, Merck, Germany) in phosphate buffer (pH 7.4). All atrial and right ventricular tissues were excised, after which the slices were weighed, fixed in a 10% formalin, and photographed.

Transparencies were projected onto a paper screen at 10-fold magnification, and the borders of the infarct, the ischemic-reperfused region, and the non-ischemic regions were traced by a blinded investigator. The corresponding areas were measured by computerized planimetry (Image J, version 1.31, NIH, Bethesda, MD). From these measurements, the infarct size was calculated (as % of the AAR).

ELISA for expression of inducible Hsp70, Hsp70 expression in left ventricular myocardium was measured using commercially available enzyme-linked immunoassay kits (#EKS-700 StressGen Biotechnologies Corp, Canada) according to the manufacturer’s instructions. Values were expressed as ng/mg protein.

Nuclear protein extract.  After 30 min of ischemia and 30 min of reperfusion, hearts were harvested. Nuclear extracts of left ventricular myocardial tissue were prepared by hypotonic lysis followed by high salt extraction [15]. Ground myocardial tissue cells were incubated in 0.5 ml ice-cold buffer (10 mM HEPES pH 7.9, 10 mM KCl, 2 mM MgCl2, 0.1 mM EDTA, 1 mM dithiothreitol DTT), containing 0.5 mM phenylmethysulfonyl fluoride (PMSF) for 15 min, after which 50 µl of NP-40 was added. After 30 sec, the mixture was centrifuged at 5,000 x g for 10 min at 4°C. The pellet was suspended in 50 µl of ice-cold buffer (50 mM HEPES pH 7.9, 50 mM KCl, 300 mM NaCl, 0.1 mM EDTA, 1 mM DTT, and 0.5 mM PMSF, with 10 % (v/v) glycerol) and incubated on ice for 30 min with frequent mixing. After centrifugation (12,000 x g, 4°C, 15 min), the supernatants were collected as nuclear extracts and stored at –80°C until use.

Electrophoretic mobility shift assay (EMSA).  An EMSA was performed using a commercial kit (Gel Shift Assay System; Promega, Madison, WI). The NF-{kappa}B consensus oligonucleotide probe (5'-AGT TGA GGG GAC TTT CCC AGG C-3') was end-labeled with [{gamma}-32P]-ATP (Free Biotech, Beijing, China) with T4-polynucleotide kinase. Nuclear protein (80 µg) was pre-incubated in a total volume of 9 µl in a binding buffer, consisting of 10 mM Tris-HCl (pH 7.5), 4% glycerol, 1 mM MgCl2, 0.5 mM EDTA, 0.5 mM DTT, 50 mM NaCl, and 0.05 mg/ml poly-(deoxyinosinic deoxycytidylic acid) for 15 min at room temperature. After adding the 32P-labeled oligonucleotide probe, the incubation was continued for 20 min at room temperature. The reaction was stoped by adding 1 µl of gel loading buffer and the mixture was subjected to non-denaturing 4% polyacrylamide gel electrophoresis in 0.5 x TBE buffer, pre-run at 300 V for 10 min. Electrophoresis was conducted at 390 V for 1 hr. After electrophoresis, the gels were transferred to Whatman DE-81 paper, dried, and exposed to autoradiographic film (Fuji Hyperfilm) with an intensifier screen at –70°C.

Statistical analysis.  The data are presented as means ± SE. Statistical analyses were performed by using SPSS version 11.01. Comparisons between groups were performed by Student’s t-test. A value of p <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Discussion
 Acknowledgement
 References
 
Attenuation of infarct size.  Representative slices of left ventricle from control and rhEPO rats at 2 hr of reperfusion are shown in Fig. 2Go. The infarct area was reduced in rhEPO group, as shown in Fig. 3Go. The AAR/total area ratio was similar in both groups (51.46 ± 3.21 for the control group and 53.65 ± 2.33 for the rhEPO group), but the infarct/AAR ratio was significantly less in the rhEPO group (15.97 ± 2.45%) than in the control group (38.56 ± 3.43%, p <0.001).



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  		Fig. 2. Representative slices of left ventricle from rats of the control and rhEPO groups after 30 min of ischemia and 2 hr of reperfusion. The slices were stained with TTC. The violet region corresponds to the non-risk area. The red region is the risk area, and the white-gray portion (outlined by a white dotted line) is the infarct area.

 


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  		Fig. 3. Left ventricular (LV) area at-risk quantification after ischemia/reperfusion. Graphic representation of the LV infarction size measured as the percentage of infarct of total ischemic area at-risk in control rats (white bar, n = 6) and in rhEPO treated rats (black bar, n = 6). Data are means ± SE. *p < 0.001 versus control group.

 
Change of Hsp70 protein level.  At 24 hr after rhEPO administration and before ischemia, the Hsp70 protein level in the left ventricle myocardium cytosol was measured by ELISA. Hsp70 levels in the rhEPO group (37.53 ± 5.11 ng/mg ) were significantly higher than in the control group (4.78 ± 0.98 ng/mg, p <0.001) (Fig. 4Go).



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  		Fig. 4. Heat shock protein 70 (Hsp70) content in rat myocardium from the control group and the rhEPO group. The rhEPO administration resulted in a significant increase in myocardial Hsp70 content (* p <0.001).

 
Change of NF-kB activation.  The EMSA measurements to evaluate NF-{kappa}B activation at 30 min of reperfusion are shown in Fig. 5Go. NF-{kappa}B bands in the control group (3.36 ± 0.26) were significantly more intense than in the sham operated group (2.41 ± 0.15, p <0.001). NF-{kappa}B bands in the rhEPO group (2.78 ± 0.16) were significantly less intense than in the control group (3.36 ± 0.26; p = 0.0034) (Fig. 6Go).



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  		Fig. 5. NF-{kappa}B binding activities of nuclear proteins in each group, shown by a representative NF-{kappa}B band in each group. Sham: sham operated group (no ischemia); Control: control group; rhEPO: rhEPO-treated group.

 


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  		Fig. 6. Relative mean intensities of all NF-{kappa}B bands in each group: Sham: sham operated group (no ischemia); rhEPO: rhEPO-treated group. Results are expressed as means ± SE (n = 6 in each group). *p <0.001, control group vs sham operated group; #p = 0.0034, rhEPO group vs control group.

 

   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
Acknowledgement
 References
 
EPO cardioprotection and its mechanism.  We found that pretreatment with rhEPO in experimental I-R enhances rat cardiac expression of Hsp70 and reduces NF-{kappa}B activation, and we corroborated findings by others that rhEPO pretreatment significantly attenuates infarct size [16,17]. Part of the mechanism for rhEPO-induced myocardial protection involves inhibition of myocardial apoptosis and preservation of ATP levels in the ischemic myocardium. Hsp70 may be one of the possible links between rhEPO and its cardio-protective effect. Recently, Yang et al [13] demonstrated that rhEPO has a protective effect on I-R injury in rat kidney and that this effect is associated with induction of Hsp70. Similarly, Sun et al [14] showed enhanced expression of Hsp27 in ischemic brain hemisphere and revealed that rhEPO reduces brain injury. In the present study, rhEPO remarkable enhanced the transcriptional expression of Hsp70 in rat myocardium at 24 hr after rhEPO administration and attenuated the infarct size.

It is still unknown how rhEPO induces Hsp70. In neuronal cells, initiation of the cascades that modulate protection by EPO and its receptor may begin with the activation of the Janus tyrosine kinase (JAK) 2 protein [10]. Subsequent downstream mechanisms appear to lead to activation of multiple signal transduction pathways that include transcription factor STAT5 (signal transducers and activators of transcription), bcl-2, protein kinase B, cysteine proteases, mitogen-activated-protein kinase, protein-tyrosine phosphatases, and NF-{kappa}B [18–21]. Hsp70 is among the stress-responsive proteins regulated by activation of the JAK/STAT pathway [22]. Activation of the JAK/STAT pathway by rhEPO may contribute to adaptation to I-R injury by up-regulating Hsp70.

The cardio-protective effect of the heat shock proteins (Hsps) against I-R injury is documented [23–25]. The protective effects of Hsps include enhanced protein folding, degradation of abnormal proteins, inhibition of apoptosis, protection of the cytoskeleton, and enhanced NO synthesis. Hsp27, Hsp70, and Hsp90 can inhibit the apoptotic process. Different Hsps inhibit this process at various points. Hsp27 has been shown to bind to cytochrome c and prevent it binding to Apaf-1 [26,27]. Conversely, Hsp90 binds to Apaf-1 and prevents its binding to cytochrome c [28], while Hsp70 prevents oligomerised Apaf-1 from recruiting pro-caspase-9 [29,30].

NF-kB in myocardial I-R injury.  Nuclear factor-kappaB is activated by myocardial ischemia and reperfusion [31–33], including in human heart subjected to cardioplegia and reperfusion during open heart surgery [34]. A detrimental role of NF-{kappa}B during reperfusion is suggested by functional studies of the genes it regulates; NF-{kappa}B inhibition of leukocyte adhesion, cytokines, and chemokines during reperfusion protects the heart against reperfusion injury [33,35–37].

The potential causative role of NF-{kappa}B activation in the manifestation of myocardial I-R injury is strongly supported by studies showing that distinct strategies including administration of decoy oligonucleotides and proteasome inhibitors reduced NF-{kappa}B activation, improved contractile function, and appeared to reduce infarct size.

More direct evidence for a detrimental role of NF-{kappa}B is supplied by Morishita et al [38], who transfected rats by the intracoronary route with a double-stranded oligonucleotide containing the NF-{kappa}B cis-element before coronary artery ligation. The decoy inhibited NF-{kappa}B activation during reperfusion and concomitantly reduced infarct size.

Heat shock response-mediated inhibition of the NF-{kappa}B pathway.  Several investigations have elucidated the proximal mechanisms by which the Hsps inhibit activation of NF-{kappa}B. In multiple cell models, prior induction of the heat shock response (HSR) inhibits subsequent activation of NF-{kappa}B [39–43]. This observation holds true whether HSR is induced by hyperthermia or nonthermal inducers. Prior induction of the Hsps inhibits degradation of I-{kappa}B{alpha} in the setting of a proinflammatory stimulus. Inhibition of I-{kappa}B{alpha} degradation, in turn, inhibits disassociation of I-{kappa}B{alpha} from NF-{kappa}B. This effect has been demonstrated in multiple cell models and in vivo. Thus, the mechanism by which the Hsp inhibits activation of NF-{kappa}B involves inhibition of I-{kappa}B{alpha} degradation and stabilization of the NF-{kappa}B·I-{kappa}B{alpha} complex. This inhibitory effect may be relatively specific for I-{kappa}B{alpha} [44]. The Hsps appear to inhibit phosphorylation of I-{kappa}B{alpha}, in large part, by inhibiting activation of I{kappa}B kinase (IKK).

The HSR appears to inhibit activation of IKK and increase intracellular phosphatase activity. These effects combine to decrease the net level of phosphorylated I-{kappa}B{alpha} in cells subjected to a proinflammatory signal. The net decrease of phosphorylated I-{kappa}B{alpha} inhibits degradation of I-{kappa}B{alpha}, NF-{kappa}B activation, and subsequent NF-{kappa}B-dependent proinflammatory gene expression.

In conclusion, we found that rhEPO pretreatment induces expression of Hsp70 and attenuates expression of NF-{kappa}B in rat myocardium and remarkably reduces the infarct size of I-R myocardium. Administration of rhEPO may provide a novel therapeutic strategy in cardio-protection of I-R injury, including in the human heart that is subject to cardioplegia and reperfusion during open heart surgery.


   Acknowledgement
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 Acknowledgement
References
 
We thank Dr. Genbao Feng for technical assistance.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 Acknowledgement
 References
 

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