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CARDIOVASCULAR
Second Department of Internal Medicine (Ta.M., Te.M., T.Y., A.T., J.S., M.T., H.K., Y.I., M.N., K.N., K.O., K.S.) and Department of Pharmacology (M.T.), Sapporo Medical University School of Medicine, Sapporo, Japan
Received September 16, 2005; accepted December 22, 2005.
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Abstract |
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). In studies using rat and rabbit hearts, recombinant human EPO as well as derivatives of EPO administered before or at the time of ischemia suppressed myocardial necrosis and apoptosis, ventricular dysfunction, and ventricular remodeling after ischemia/reperfusion (IR) (Calvillo et al., 2003; Moon et al., 2003; Parsa et al., 2003; Lipsic et al., 2004; Wright et al., 2004; Fiordaliso et al., 2005). Furthermore, these studies consistently showed that the phosphatidylinositol 3-kinase (PI3K)-Akt pathway plays a crucial role in the EPO-induced cardioprotection (Parsa et al., 2003; Cai and Semenza, 2004; Bullard et al., 2005; Hanlon et al., 2005; Rafiee et al., 2005), although involvement of mitogen-activated protein kinase, protein kinase C (PKC), and mitochondrial ATP-sensitive K+ channel (mitoKATP channel) has also been suggested (Shi et al., 2004; Bullard et al., 2005; Hanlon et al., 2005; Rafiee et al., 2005). However, because normal myocardium was used in all these previous studies to assess EPO-induced alteration in response to I/R injury, it remains unknown whether EPO can afford cardioprotection to diseased hearts.
In the present study, we assessed whether EPO protects the myocardium in postinfarct hearts with ventricular remodeling. Myocardial infarction provokes remodeling of the heart over a period of several weeks or months, resulting in hypertrophy and interstitial fibrosis in the noninfarcted regions and dilation of the left ventricle. Intracellular signaling pathways responsible for the postinfarct remodeling potentially interact with intracellular signaling that induces cytoprotection. In fact, our previous studies have demonstrated that postinfarct ventricular remodeling made the myocardium refractory to ischemic preconditioning (PC) by disrupting signal transduction from the G-protein-coupled receptor to PKC-
(Miki et al., 2000, 2003). Because there are overlaps in signaling pathways provoked by PC and activated EPO receptors (Fisher, 2003; Smith et al., 2003; Yellon and Downey, 2003), it is possible that signals relevant to the remodeling process may also interfere with the mechanism of EPO-induced protection. Results of the present study suggest that postinfarct remodeling impairs the signaling pathway from activated EPO receptors to the PI3K-Akt pathway, but that a compensatory mechanism upstream of guanylyl cyclase maintains the infarct size-limiting effect of EPO.
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Materials and Methods |
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Preparation of Myocardial Infarction and Isolated Heart Perfusion
Male Sprague-Dawley rats (8–10 weeks old) were anesthetized with a mixture of ketamine (90 mg/kg i.p.) and xylazine (10 mg/kg i.p.). The rats were intubated with an endotracheal tube and ventilated using a Harvard respirator (model 683; Harvard Apparatus Inc., South Natick, MA) with supplemented oxygen. After a left thoracotomy, a 5.0 silk thread was passed around a marginal branch of the left coronary artery. Rats were then divided into two groups: sham and post-MI groups. In the sham group, the coronary artery was not ligated. In the post-MI group, the coronary branch was permanently ligated to induce myocardial infarction. The surgical wounds were repaired, and 10 mg of ampicillin and 10 mg of cloxacillin were injected intramuscularly for prophylaxis of infection, and the rats were then returned to their cages for recovery. Four weeks (protocol 1) or 2 weeks (protocol 2) after surgery, each rat was brought into the laboratory and reanesthetized with sodium pentobarbital (80 mg/kg i.p.), and the heart was quickly excised for isolated heart preparation. In 28 randomly selected rats (13 rats in the sham group and 15 rats in the 4-week post-MI group), systemic blood pressure and pulse rate were measured in a conscious state using the tail-cuff method (BP-98A; Softran, Tokyo, Japan), and blood samples were collected from the tail vein before isolation of the heart. Plasma EPO level was determined by a radioimmunoassay (Recombigen EPO kit; Mitsubishi Kagaku Iatron, Tokyo, Japan). The excised heart was perfused at a pressure of 75 mm Hg with noncirculating Krebs-Henseleit buffer (118.5 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 1.2 mM KH2PO4, 24.8 mM NaHCO3, 2.5 mM CaCl2, and 10 mM glucose). The buffer was gassed with 95% O2, 5% CO2, and the temperature of the perfusate was maintained at 37°C. A fluid-filled latex balloon with a polyethylene-50 tube was inserted into the left ventricle and was connected to an SCK-580 transducer (Nihon-Kohden, Tokyo, Japan). Coronary flow was measured by timed collection of perfusate dripping from the heart.
Experimental Protocol and Measurement of Infarct Size
Protocol 1. In this protocol, hearts isolated 4 weeks after surgery were examined. After a 20-min stabilization period, all hearts were subjected to 25-min global ischemia and 2-h reperfusion. Before global ischemia, each heart in the sham group was subjected to one of eight treatments: no pretreatment (control); infusion of 5 U/ml recombinant human EPO; 5 µM LY294002, a PI3K inhibitor; EPO plus LY294002; 2 µM ODQ, a guanylyl cyclase inhibitor; EPO plus ODQ; 100 µM 5-HD, a blocker of mitoKATP channel; or EPO plus 5-HD. In the post-MI group, each heart was subjected to no pretreatment (control); EPO; EPO plus LY294002; EPO plus 100 nM wortmannin, another PI3K inhibitor; EPO plus ODQ; or EPO plus 5-HD. EPO and each inhibitor were infused for 15 min commencing 15 min before the global ischemia.
Protocol 2. Because results of protocol 1 showed that EPO-induced protective mechanisms were altered at 4 weeks after infarction (see Results), we examined whether such alteration in myocardial response to EPO develops during the earlier period after infarction. In this protocol, rat hearts were isolated at 2 weeks after coronary ligation and subjected to no pretreatment (control), infusion of EPO, or EPO plus LY294002. Doses of EPO and LY294002 and timings of infusion of these agents were the same as those in protocol 1. All hearts in this protocol were used for infarct size experiments. After 2 h of reperfusion, hearts were weighed, frozen, and cut into 1.5-mm-thick sections from apex to base. Infarcts in the heart slices were visualized by tetrazolium staining as reported previously (Miki et al., 2000, 2003; Tanno et al., 2000). Fresh infarcts, scar areas because of coronary ligation, and outlines of the ventricle were traced on a clear acetate sheet. The scarred infarct because of coronary ligation was transmural and clearly distinguished from other areas of the left ventricle (Fig. 1), and the scar area was excluded from infarct size measurement.
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0.3 g) were taken from the isolated perfused hearts using sharp ophthalmology scissors at baseline, at 15 min after EPO infusion or after 25-min ischemia/5-min reperfusion. In the post-MI group, tissues for immunoblotting were taken from the lateralposterior wall because scarred infarct was located in the anterior wallseptum of the ventricle. Thus, tissues were sampled from the same regions in the sham group. We carefully excluded border zone tissues (i.e., apparently viable tissues within 1 mm next to scarred infarct) from tissue samples in the post-MI group. Because scarred regions were clearly distinguished from viable myocardium at 4 weeks after the coronary ligation, it was easy to obtain tissue samples exclusively from the noninfarcted areas in rat hearts. The tissues were frozen immediately after sampling in liquid nitrogen and stored at –80°C until biochemical analysis. Frozen heart samples were homogenized in ice-cold buffer containing 20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM 
-glycerophosphate, 1 mM Na3VO4, 1 µg/ml leupeptin, 50 µg/ml phenylmethylsulfonyl fluoride, and a protease inhibitor cocktail tablet (Complete; Roche Applied Science, Penzberg, Germany). The homogenate was centrifuged at 13,000g for 15 min to obtain the supernatant. Protein concentration was determined using a Bio-Rad Protein Assay kit (Bio-Rad, Hercules, CA). Equal amounts of protein were analyzed by immunoblot assays with the use of antibodies that recognize the following: EPO receptor, suppressor of cytokine signaling (SOCS)-1 and SOCS-3 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), phosphorylated JAK2 (Tyr1007/1008) and total JAK2, phosphorylated Akt (Ser473) and total Akt, and phosphorylated eNOS (Ser1177) and total eNOS (Cell Signaling Technology, Danvers, MA). After detection of phosphorylated proteins, PVDF membranes were stripped from their bound antibodies using a Re-blot Western blot recycling kit (Chemicon, Temecula, CA). The membranes were then blotted with antibodies to total JAK2, Akt, or eNOS. Levels of proteins in immunoblots were determined by densitometric analysis using SigmaGel (SPSS Inc., Chicago, IL). Equal loading of protein onto each lane in the gel was confirmed later from comparable levels of vinculin detected by reblotting with an anti-vinculin antibody (Sigma-Aldrich, St. Louis, MO) and/or comparable densitometric levels of 116-kDa bands (which correspond to vinculin) in the gels stained with Coomassie Brilliant Blue.
Chemicals
LY294002 was purchased from Calbiochem (Darmstadt, Germany), and ODQ, 5-HD, and wortmannin were obtained from Sigma-Aldrich. Recombinant human EPO was kindly provided by Chugai Pharmaceutical Co. (Tokyo, Japan).
Statistics
All data are presented as means ± S.E.M. One-way analysis of variance combined with the Student-Newman-Keuls post hoc test was used to test for differences in heart weight, plasma EPO level, and infarct size between treatment groups. Repeated measures analysis of variance was used to test for differences in cardiac functions in any given group. These statistical analyses were performed by using SigmaStat (SPSS Inc.). The difference was considered significant if the P value was less than 0.05.
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Results |
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There were no significant differences in the numbers of white blood cells, red blood cells, and platelets between the sham and post-MI groups (Table 1). Plasma EPO level in the sham group was 14.5 ± 1.1 mU/ml, and the level was not changed at 4 weeks after MI. Mean blood pressures and heart rates in situ before isolation of the hearts at 4 weeks after surgery were also similar in the two groups. Heart weight, however, was significantly larger in the post-MI group than in the sham group, indicating ventricular remodeling after MI (Table 1).
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Data on Cardiac Functions |
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In the post-MI hearts, baseline heart rate, LVDP, and coronary flow were comparable in pretreatment groups, although LVDP in the post-MI hearts was slightly lower than that in the sham-operated hearts (Table 3). LVDP and coronary flow after reperfusion were decreased in all pretreatment groups as in the sham group.
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Protocol 2. Under baseline conditions, heart rate, LVDP, and coronary flow levels were 278 ± 7 bpm, 103 ± 7 mm Hg, and 17.7 ± 0.5 ml/min, respectively, in post-MI hearts entered this protocol. Alterations of these parameters after ischemia/reperfusion were similar to those observed in post-MI hearts in protocol 1 (data not shown).
Infarct Size Data
Protocol 1. As shown in Table 4, risk area sizes were comparable in the hearts in the sham and post-MI groups that were subjected to pretreatments. In the sham group, pretreatment with EPO significantly reduced infarct size as a percentage of risk area (%I/R) from 59.9 ± 4.1% in controls to 36.2 ± 4.2%. This EPO-induced protection was blocked by LY294002, ODQ, or 5-HD, although these blockers by themselves did not modify infarct size. In the post-MI group, there was no significant difference in the sizes of scarred infarct, ranging from 12 to 19% of the left ventricular mass. These sizes of scarred infarcts seem to be small but actually are underestimates of infarct sizes at the acute phase, because both thinning of scarred infarct and hypertrophy of noninfarct myocardium during the period of 4 weeks after infarction should have reduced volume percentages of the infarcted region. In the post-MI group, size of infarct after 25-min ischemia with no pretreatment (%I/R in control = 58.1 ± 5.0%) was comparable with that in the sham group. EPO limited infarct size (%I/R = 35.2 ± 4.0%) as in the sham group, and this infarct size-limiting effect of EPO was insensitive to PI3K inhibitors; neither LY294002 nor wortmannin abolished the EPO-induced infarct size limitation. ODQ and 5-HD abolished the EPO-induced protection in the post-MI hearts as in the sham-operated hearts. After completion of this protocol, we additionally used three post-MI hearts to assess effects of LY294002 alone on infarct size. In this LY294002-treated post-MI group, %I/R was 61.6 ± 4.1%, which was similar to the %I/R level in the post-MI controls.
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Using separate groups of rats, we examined the effect of PC on infarct size in the post-MI group to confirm that postinfarct ventricular remodeling impairs the PC mechanism in rat hearts as we reported for rabbit hearts (Miki et al., 2000, 2003). As expected, PC with two cycles of 5-min ischemia/5-min reperfusion failed to limit infarct size (%I/R = 53.1 ± 5.2%; n = 3) in the post-MI hearts.
Protocol 2. Heart weight was 1.74 ± 0.03 g in the rats 2 weeks after MI, which was only slightly smaller than the heart weight at 4 weeks after MI (protocol 1), suggesting that substantial remodeling had occurred during a 2-week postinfarct period in the rats. EPO significantly reduced %I/R from 65.0 ± 5.8 to 39.8 ± 4.5%. This EPO-induced protection was not blocked by LY294002 (Table 4).
Immunoblot Assays
EPO receptor protein was detected in the rat myocardium (Fig. 2), and its level was not altered by postinfarct ventricular remodeling or acute I/R. There was no significant difference in levels of total JAK2, total Akt, and total eNOS in the study groups; thus, levels of phospho-JAK2, phospho-Akt, and phospho-eNOS were normalized by their total protein levels. EPO increased the level of phospho-JAK2 in sham hearts, but the increase in phosphorylation levels of JAK2 by EPO was significantly attenuated in post-MI hearts (Fig. 3). The baseline level of phospho-Akt was not different in the sham-operated and post-MI hearts. As shown in Fig. 4A, EPO significantly increased the level of phospho-Akt in sham hearts, and this increase was completely blocked by coinfusion of LY294002. The level of phospho-Akt was elevated after I/R compared with the baseline level in the sham group, and this Akt phosphorylation was not enhanced by pretreatment with EPO (Fig. 4B). However, such phosphorylation of Akt by EPO was not observed in the post-MI hearts. EPO tended to increase phospho-eNOS levels both in the sham and MI groups, and this change was diminished by LY294002 in the sham group but not in the MI group (Fig. 5A). There was no significant difference between phospho-eNOS levels after I/R in EPO-treated and untreated hearts (Fig. 5B). SOCS-1 and SOCS-3 levels were higher by 54 and 12%, respectively, in the post-MI group than in the sham group, although only the difference in SOCS-1 levels was statistically significant (Fig. 6). I/R with or without EPO pretreatment did not modify the levels of SOCS-1 and SOCS-3.
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Discussion |
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, 2005; Oldenburg et al., 2004; Costa et al., 2005), were thought to participate in EPO-induced protection in both the normal myocardium and remodeled myocardium.
EPO has been shown to activate a number of cell survival pathways, including those mediated by JAK-signal transducer and activator of transcription, PI3K-Akt, ERK1/2, and PKC (Parsa et al., 2003; Smith et al., 2003; Cai and Semenza, 2004; Shi et al., 2004; Bullard et al., 2005; Hanlon et al., 2005; Rafiee et al., 2005). Although the role of each of these signaling molecules in EPO-induced protection has not been completely clarified, contribution of the PI3K-Akt pathway to the myocardial protection is supported by a number of earlier findings (Parsa et al., 2003; Cai and Semenza, 2004; Bullard et al., 2005; Hanlon et al., 2005; Rafiee et al., 2005). For example, in a study by Parsa et al. (2003), EPO administration resulted in activation of JAK1, signal transducer and activator of transcription 3, Akt, and ERK1/2 in H9c2 cells 15 to 60 min after administration, and EPO-induced reduction in anoxic cell death was eliminated by a PI3K inhibitor but not by an ERK inhibitor. Consistent with these previous findings, 15-min infusion of EPO induced Akt phosphorylation and cardioprotection, both of which were sensitive to LY294002, a PI3K inhibitor, in normal (i.e., sham-operated) hearts in this study (Fig. 4; Table 4). However, such EPO-induced Akt activation was not detected in the myocardium remodeled 4 weeks after infarction (Fig. 4), although EPO protected the myocardium from infarction. Furthermore, neither LY294002 nor wortmannin inhibited the EPO-induced protection in post-MI hearts. Failure of LY294002 to abolish the infarct size-limiting effect of EPO was observed also in the hearts 2 weeks after infarction, suggesting that response of Akt to EPO receptor activation is impaired at the early phase of postinfarct ventricular remodeling.
The mechanism by which myocardial PI3K/Akt lost response to EPO receptor stimulation after development of postinfarct remodeling remains unclear. However, down-regulation of EPO receptor expression can be excluded from possible mechanisms, because the level of the EPO receptor protein was not reduced in the myocardium remodeled 4 weeks after infarction (Fig. 2). One explanation is that up-regulated SOCS proteins suppressed signaling from activated EPO receptors to PI3K. SOCS is a family consisting of eight proteins that function as suppressors of cytokine signaling, and SOCS-1 and SOCS-3 have been shown to negatively regulate JAK activation by EPO and other cytokines (Jegalian and Wu, 2002; Tan and Rabkin, 2005). Indeed, activation of JAK2 by EPO was significantly attenuated in the remodeled myocardium (Fig. 3), in which SOCS-1 level was significantly elevated by 50% (Fig. 6). The level of SOCS-3, which is known to be up-regulated by angiotensin II (Calegari et al., 2003, 2005), was slightly higher in the myocardium after 4 weeks of remodeling than in the control, but this difference was not statistically significant. The reason for SOCS-1 selective up-regulation in the present model of postinfarct remodeling remains to be investigated. Activation of the TNF-
receptor might have been involved in the SOCS-1 up-regulation, because the serum level of TNF- and myocardial TNF- mRNA level were shown to be elevated in rats after myocardial infarction (Ono et al., 1998; Berthonneche et al., 2004; Schulz et al., 2004; Tan and Rabkin, 2005).
Despite lack of Akt activation, EPO afforded cardioprotection against infarction to postinfarct hearts, and the extent of cardioprotection was equivalent to that in the normal myocardium. These results suggest that there is a mechanism in postinfarct hearts to compensate the lack of signal input from the activated PI3K-Akt pathway, sending signals to downstream mediators of cell protection. As an important mechanism of cell protective signals distal to Akt, opening of the mitoKATP channel by protein kinase G (PKG) has been suggested by a series of studies on mechanisms of PC against infarction (Krieg et al., 2004, 2005; Oldenburg et al., 2004; Costa et al., 2005). Krieg et al. (2004) showed that an Akt inhibitor and transfection of dominant negative Akt abolished NO-mediated activation of the mitoKATP channel in response to PC triggered by bradykinin receptors. A recent study by Costa et al. (2005) demonstrated opening of the mitoKATP channel in isolated mitochondria by addition of exogenous active PKG. Furthermore, it has been reported that EPO was capable of stimulating NO production in the rat hippocampus and endothelial cells (Beleslin-Cokic et al., 2004; Yamamoto et al., 2004). Unfortunately, we could not demonstrate significant elevation of phospho-eNOS level by EPO, although there was a trend for increase by 10% in the present study. However, a larger difference may have been detected at later time points as it was in a study by Bullard et al. (2005), who observed a 2-fold increase in phospho-eNOS induced by EPO in rat hearts 15 min after reperfusion, and the possibility of involvement of other NO-producing mechanisms also cannot be excluded. Nevertheless, we found for the first time that ODQ, a guanylyl cyclase inhibitor, abolished cardioprotection afforded by EPO similarly in both sham-operated and postinfarct hearts. Furthermore, this effect of ODQ was mimicked by 5-HD, a mitoKATP channel blocker. Together with the results obtained by using PI3K inhibitors, these findings provide pharmacological evidence supporting the notion that PKG-mediated opening of the mitoKATP channel is downstream of PI3K-Akt in EPO-induced cardioprotection and that compensation for the lack of Akt activation in postinfarct hearts is induced upstream of guanylyl cyclase.
It has been reported that EPO induced intracellular translocation of PKC- in buffer-perfused rabbit and rat hearts and that the infarct size-limiting effect of EPO was blocked by chelerythrine, a selective PKC inhibitor, indicating contribution of PKC to EPO-induced protection (Shi et al., 2004; Hanlon et al., 2005; Rafiee et al., 2005). PKC- is thought to elicit opening of the mitoKATP channel, leading to cardioprotection (Sato et al., 1998; Yellon and Downey, 2003). However, our previous studies (Miki et al., 2000, 2003) have shown that PC fails to elicit PKC- translocation and enhancement of anti-infarct tolerance in rabbit hearts remodeled after infarction. We confirmed lack of myocardial response to PC in postinfarct rat hearts also using infarct size as an endpoint. Therefore, it is unlikely that PKC is involved in maintenance of myocardial response to EPO in postinfarct hearts.
In the present study, EPO was infused before ischemia and responses of signaling molecules during the pretreatment period were correlated with infarct tolerance of the myocardium. No significant difference was detected in the level of phospho-Akt upon reperfusion between the control group and EPO-pretreated group, although infarct size was significantly smaller in the EPO-treated group. However, efficacy of EPO for suppressing lethal reperfusion injury has been examined recently in several studies (Lipsic et al., 2004; Bullard et al., 2005; Hanlon et al., 2005). Administration of EPO at the time of reperfusion resulted in infarct size limitation to an extent similar to that achieved by pretreatment with EPO in those studies (Lipsic et al., 2004; Hanlon et al., 2005). Furthermore, the importance of activation of signaling pathways at the time of reperfusion, including the PI3K-Akt pathway, for myocardial salvage has been suggested in cardioprotection afforded by preconditioning (Hausenloy and Yellon, 2004). These findings suggest the possibility of clinical use of EPO for patients with acute myocardial infarction as an adjunct therapy to coronary reperfusion. Furthermore, a study by Namiuchi et al. (2005) showed that serum EPO level was an independent predictor for cumulative creatine kinase release in patients with first acute myocardial infarction, suggesting a cardioprotective role of endogenous EPO. In the present rat preparation, the role of endogenous EPO in protection against ischemic injury could not be assessed because plasma EPO level was not significantly changed 4 weeks after infarction. The effects of EPO administration at the time of reperfusion on myocardial necrosis and cell signaling in hearts remodeled after infarction warrant further investigation.
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Footnotes |
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ABBREVIATIONS: EPO, erythropoietin; IR, ischemia/reperfusion; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PC, ischemic preconditioning; mitoKATP channel, mitochondrial ATP-sensitive K+ channel; MI, myocardial infarction; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; ODQ, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one; 5-HD, 5-hydroxydecanoate; SOCS, suppressor of cytokine signaling; JAK, Janus kinase; eNOS, endothelial nitric-oxide synthase; LVDP, left ventricular developed pressure; bpm, beats per minute; %I/R, infarct size as a percentage of risk area; ERK, extracellular signal-regulated kinase; TNF-, tumor necrosis factor ; PKG, protein kinase G; HR, heart rate.
Address correspondence to: Dr. Tetsuji Miura, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: miura{at}sapmed.ac.jp
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