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Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland
Submitted 12 August 2005 ; accepted in final form 5 October 2005
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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0.05), and these changes were not different from the response triggered by PC (n = 5 hearts/treatment group). Phosphorylation of downstream p70S6K was also equivalent in PC and Postcon groups. These data do not support the hypothesis that application of 30-s cycles of repetitive ischemia during reperfusion exerts a protective effect on pig hearts subjected to lethal ischemia, but this is not due to a failure to phosphorylate ERK and Akt during early reperfusion.
swine; signal transduction; extracellular signal-regulated kinase 1/2; infarction; ischemic preconditioning
PC triggers a protein kinase cascade that includes various isoforms of PKC, tyrosine kinases, and members of the MAPK family that appear to mediate the protection (3). Activation of certain prosurvival kinases, such as the phosphatidlylinositol 3-kinase (PI3K)-Akt and the MAPK p42/p44 ERK1/2, has been recently shown to be important in PC-induced cardioprotection (8, 12, 13, 30, 32, 33, 35). Some evidence supports the involvement of these pathways also in Postcon. In situ (37) and isolated perfused (6) rabbit hearts were not protected by Postcon when ERK1/2 was inhibited, whereas Postcon could not protect isolated rat (34) or rabbit (36) hearts when the Akt-PI3K pathway was inhibited.
We assessed the hypothesis that Postcon applied during early reperfusion is as cardioprotective as PC in pigs by limiting lethal injury using an open-chest model of ischemia and reperfusion. Additionally, we assessed whether common signaling pathways are evoked by these two triggering events that include phosphorylation of Akt, ERK1/2, and p70S6K during early reperfusion (Fig. 1).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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These protocols were approved by the Institutional Animal Care and Use Committee of the Uniformed Services University of the Health Sciences and conformed to the standards in the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH Publications No. 85-23, Revised 1996). Yorkshire pigs of either sex, weighing between 18 and 22 kg and free of clinically evident disease, were entered into this study.
Pigs were sedated with an intramuscular injection of 15 mg/kg ketamine hydrochloride (Vetalar, Fort Dodge) and anesthetized with pentobarbital sodium (30 mg/kg, Sigma; St. Louis, MO). Pigs were placed on a homeothermic blanket control unit (Harvard Apparatus; Holliston, MA) designed to maintain a core body temperature of at least 37°C, as measured by a thermister probe placed in the rectum. Interanimal variation in temperature was minimized with careful monitoring.
A tracheotomy was performed, and pigs were mechanically ventilated (Harvard) with room air supplemented with oxygen. A saline-filled catheter was placed in the right external jugular vein for drug administration and fluid infusion. A 9-Fr catheter introducer (Catheter Sheath Introducer System, Cordis; Miami, FL) was placed in the right carotid artery. Through this introducer catheter, a Mikro-Tip dual-pressure transducer catheter (model SPC-780C, Millar) was inserted to measure aortic and ventricular pressure and to permit simultaneous electronic differentiation to yield the change in pressure over change in time (dP/dt). End-tidal CO2 was monitored continuously (Hewlett-Packard, model 78356A; Palo Alto, CA), arterial blood gases were measured periodically, and ventilatory parameters were adjusted as needed to maintain blood gases within physiological ranges. Slow intravenous infusion of normal saline maintained hydration throughout the surgery, and additional anesthetic was administered as needed.
A left thoracotomy was performed in the fourth intercostal space. The heart was suspended in a pericardial cradle, and the left anterior descending (LAD) coronary artery was isolated distal to the first or second diagonal branch. A strip of moistened umbilical tape was passed around the vessel for later coronary occlusion, which was accomplished by snaring it into a small plastic tube that allowed visualization of the occluded artery within it. Ischemia was verified by the development of a sharply defined region of cyanosis and ECG changes. Reperfusion was verified by the appearance of reactive hyperemia in the previously occluded region. The chest incision was covered with moistened gauze to prevent desiccation and to provide thermal insulation.
Aortic and left ventricular blood pressure, left ventricular dP/dt, lead I of the ECG, and core body temperature were measured throughout the experiment and recorded by using a Gould RS3800 Recorder (Gould; Cleveland, OH) and MacLab System (Apple Computer; Cupertino, CA). The pigs were allowed at least 20 min after surgical preparation to return to a steady state before experimentation.
Experimental Design
Two series of studies were performed. In the first (infarct) series, the potential for Postcon to limit infarct size similarly to PC was assessed by using our established model of ischemia and reperfusion. In the second (protein) series, altered expression and phosphorylation of Akt, ERK-1/2, and p70S6K were assessed during the final reperfusion phase. All pigs were assigned to one of three treatment groups (Fig. 2). All animals were subjected to a 30-min test period of regional ischemia followed by 3 h (infarct series) or 15 min (protein series) of reflow. Blood gases, hematocrit, hemodynamics, ECG, and temperature were measured before treatment, after treatment, midway into the test episode of ischemia, and throughout reflow.
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Infarct series. At the completion of the 3-h final reperfusion period, heparin (5,000 units) and an additional 10 mg/kg of pentobarbital sodium were administered intravenously. The hearts were excised rapidly and processed for postmortem analysis of the area at risk (AAR) and infarct size using triphenyltetrazolium chloride macrochemistry as described in detail previously (28) (n = 7 pigs/treatment group).
Protein series. At the completion of the 15-min final reperfusion period, an additional 10 mg/kg pentobarbital sodium was administered intravenously. The hearts were rapidly removed (2–3 s) by cutting across the atrioventricular groove with a sharp knife, and transmural nonischemic (supplied by the left circumflex artery) and ischemic regions (supplied by the LAD coronary artery) were sampled using a sharp, single-edged razor blade and further divided into subendocardial, midmyocardial, and subepicardial thirds of myocardium. Samples were quickly frozen (within 7–10 s of complete heart excision) in freon cooled to the temperature of liquid nitrogen, powdered, and stored at –70°C until analysis. Tissue was assayed for total and phosphorylated Akt (or PKB), ERK1/2, and p70S6K (n = 5 pigs/treatment group).
Western Blot Analysis
Samples of frozen cardiac powdered tissue (50-mg samples) were sonicated on ice in 200 µl fresh radioimmunoprecipitation assay lysis buffer containing 50 mM Tris·HCl (pH 8.0), 0.1% SDS, 0.5% sodium deoxycholate, 1% Nonidet P-40, 150 mM NaCl, 1 µM NaF, 2 µM Na3VO4, 10 µM 
-glycerophosphate, and 1 mini protease inhibitor cocktail tablet (Roche). The sonicated samples were then centrifuged at 13,000 rpm for 20 min at 4°C, and the pellet was discarded. Total protein concentrations of the supernatants were determined by using a bicinchoninic acid protein reagent kit (Pierce; Rockford, IL), with bovine serum albumin as a standard. Samples containing equal amounts of protein (30 µg) were prepared and separated by SDS-PAGE using the NuPAGE gel system and 4–12% Bis-Tris Gels (Invitrogen; Carlsbad, CA) according to the manufacturer's instructions. The resolved proteins were transferred electrophoretically to nitrocellulose membranes (Invitrolon PVDF, Invitrogen; Carlsbad, CA) at 15 V for 10 h in a cold room using a NuPAGE transfer buffer (Invitrogen) with 10% methanol.
The nitrocellulose membranes were incubated 1 h in TBS-T (0.9% NaCl, 10 mmol/l Tris, and 0.1% Tween-20), supplemented with 5% milk to reduce nonspecific binding and incubated for 2 h at room temperature with a 1:5,000 dilution of anti-Akt antibody (rabbit, Cell Signaling; Beverly, MA), 1:5,000 dilution of anti-phospho-AktSer473 (Cell Signaling), 1:10,000 dilution of anti-ERK1/2 (mouse, BD Bioscience; San Diego, CA), 1:10,000 dilution of anti-phospho-ERK1/2Thr202/Tyr204 (BD Biosciences), 1:2,500 dilution of anti-p70S6K (Cell Signaling), 1:1,000 dilution of anti-phospho-p70S6KThr389 (Cell Signaling), and 1:2,500 dilution of anti-phospho-p70S6KThr421/Ser424 (Cell Signaling). The membranes were then washed and exposed to secondary antibody (Akt and phospho-Akt, goat anti-rabbit; ERK and phospho-ERK, goat anti-mouse; and p70S6K and phospho-p70S6K, goat anti-rabbit) immunoglobulin G conjugated with horseradish peroxidase (Cell Signaling), diluted 1:5,000 for Akt, phospho-Akt, p70S6K, and phospho-p70S6K and 1:10,000 for ERK and phospho-ERK for 1 h at room temperature. Sites of antibody-antigen reaction were visualized, and the detection of signal was determined by using enhanced chemiluminescence (ECL Plus, Amersham, Piscataway, NJ) before exposure to photographic film. The developed films were scanned, and the band densities were quantified by densitometry (NIH Image v1.62 analysis software, NIH). Data for ERK and phospho-ERK represent the sum of the 42- and 44-kDa bands for each sample.
For all experiments, control minigels were run before Western blot analysis and stained with Coomassie brilliant blue (Bio-Rad; Hercules, CA), and several representative bands were quantified by densitometry to ensure equality of loading. Equal protein loading in each lane was confirmed by probing for -actin. Adequate transfer of proteins from the gel to the membrane was confirmed by Coomassie blue staining of the gel and Ponceau red staining (Sigma) of the membrane.
Data Analysis
Values are means ± SE, and data were analyzed with SPSS for Windows (v12.0.2; SPSS; Chicago, IL). Differences between groups were compared with ANOVA using the Student-Newman-Keuls multiple-comparison posttest analysis. ANOVA with repeated measures tested differences within groups over time. In the infarct series, AAR and the animal's core temperature are independent predictors of infarct size (28) in this model. To control for variation in the AAR, the size of the infarction was expressed as a percentage of this area. To control for the variation in temperature, differences in the relationships between infarct size and temperature were analyzed by using analysis of covariance (ANCOVA) using infarct size as the dependent variable and temperature as the independent covariate. The observed densitometry of the band of interest in immunoblots was normalized to that of the band for -actin in the same sample. All band densities for proteins of interest were then normalized to the mean of the control group to facilitate comparisons, such that the mean for the control tissues was defined as 1 arbitrary unit ± SE. Statistical comparisons were made by use of unpaired Student's t-test. For all analyses, P 0.05 was considered statistically significant.
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RESULTS |
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Hemodynamic data are summarized in Table 1. Baseline heart rate, systolic and diastolic pressure, and left ventricular rate-pressure product were not significantly different among the various groups, and PC and Postcon did not differ from control at any measurement period. The rectal temperature was maintained within ±1° of 38.0°C and did not vary among groups.
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Heart weight, body weight, AAR, and infarct size expressed as both a percentage of the left ventricle and as a percentage of the AAR are provided in Table 2. Expression of infarct size as a percentage of the left ventricle accounts only for the variability in heart size. Expression of infarct size (as %AAR) normalizes for variability in the size of the myocardial region that is rendered ischemic, a baseline predictor of infarct size, and improves precision of estimated effects of treatments. Thirty minutes of ischemia resulted in an infarct size of 26.5 ± 5.2% of the AAR for infarction, and this was dramatically limited by PC to only 2.8 ± 1.2%. Postcon with three episodes of 30 s of reperfusion followed by 30 s of ischemia had no effect on infarct size in this pig model, and infarct size averaged 37.8 ± 5.1%, which was not different from the control group. Because temperature is also a baseline predictor of infarct size and can contribute to sample variability and potentially obscure treatment effects, we further analyzed the data to account for this additional variable. As shown in Fig. 3, comparison of treatments using an ANCOVA with temperature as the covariate confirmed that Postcon did not limit infarct size, although PC did confer significant cardioprotection.
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Effect of PC and Postcon on Protein Modulation
Results of immunoblot staining for total and phosphorylated forms of Akt, ERK1/2, and p70S6K in localized regions of ischemic and nonischemic myocardium harvested from control and experimental animals are listed in Table 3. The effects of PC and Postcon were transmurally variable with the greatest phosphorylation occurring in the inner and middle thirds of the myocardium and little or no change evident in the subepicardium.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The powerful phenomenon of PC was first described by Murry et al. (23) and has consistently been shown to occur within all species tested to date. The application of brief, transient periods of nonlethal ischemia before a subsequent lethal episode of ischemia markedly delays the development of infarction. Although potentially useful within settings in which an ischemic event can be predicted, its utility within settings that do not provide time for pretreatment is unclear.
Postcon was first described by Zhao et al. (38) and offered a novel approach to myocardial protection. Exposure to several cycles of coronary occlusion and reperfusion after a sustained ischemic insult in an in vivo dog model indicated a reduction in multiple manifestations of injury, including infarct size, endothelial dysfunction, and reduced neutrophil accumulation. Subsequent studies in dogs (10), rabbits (37), and rats (17, 34) have confirmed this initial report. Whether or not reported Postcon protection is as potent as PC or utilizes complementary pathways in an additive manner is unclear. Although combined PC and Postcon induced additive protection in the rabbit (37), these combined treatment protocols did not produce additive protective effects in the rat (34) or dog (10), implying potentially overlapping mechanisms. However, the results of the current studies indicate that clinical utility of Postcon strategies may be limited by differences between species and sensitivity to protocols and may depend on a detailed understanding of the sequence of events that ultimately imparts protection.
Whether alternative Postcon protocols could have resulted in protection in the in vivo pig model utilized in these studies is unclear. The time course and treatment dosage of Postcon were selected based on the protective results demonstrated in the dog (10, 38), a species of similar size but significantly different from the pig in terms of a number of anatomical, physiological, and biochemical indexes. Doubling the Postcon stimulus to six cycles of ischemia and reperfusion also had no protective effect. Additionally, Postcon was initiated within the first minute of reperfusion that has been identified as critical to realize the protective effect of Postcon (17). Nonetheless, several studies now indicate that certain protocol details affect the potency of Postcon to effectively protect the myocardium in different species. For example, in rat and mouse myocardium, 10-s episodes of ischemia and reperfusion are required for protection (16, 17). Thus the results of the current studies emphasize that care must be taken to extrapolate findings concerning Postcon among species and warn that apparent minor variation in experimental strategies and protocols may markedly affect the acquisition of the protected state. Whether this delicate sensitivity to protocol can eventually translate to a useful clinical model remains to be determined and may depend on a thorough elucidation of the signaling pathways involved in cardioprotection.
Certain components of the cellular prosurvival PI3K-Akt pathway are known to be activated in response to PC (13), as well as PC induced pharmacologically by acetylcholine and bradykinin (18). Akt, also referred to as PKB or Rac, is thought to play a role in controlling the balance between survival and apoptosis by means of its ability to phosphorylate and inactivate several targets (7, 19). Studies in isolated-perfused rat (34) and rabbit (36) hearts, as well as an in vivo rabbit model (37), have implicated a mechanistic role in Postcon for activation of the PI3K-Akt pathway and its downstream targets endothelial nitric oxide synthase (eNOS) and p70S6K (34). In these studies, phosphorylation of pathway components occurred within the first few minutes of reperfusion, and wortmannin or LY-294002, inhibitors of PI3K, completely blocked the reduction in infarct size and phosphorylation induced by Postcon. However, a recent study (6) in isolated-perfused rabbit hearts did not support a role for PI3K-Akt signaling using the same signaling pathway blockers. We demonstrated equivalently increased phosphorylation of Akt during reperfusion and similar patterns of p70S6K phosphorylation in both PC- and Postcon-treated hearts after a lethal episode of ischemia in the pig. However, these phosphorylation changes were not associated with cardioprotection in Postcon myocardium. Insufficient activation or inactivation of these signaling pathway components to a critical threshold by choosing a Postcon protocol that was inappropriate for the species cannot explain the lack of cardioprotection observed by Postcon, because PC produced similar levels of ERK and Akt activation but was protective. Thus activation of the PI3K-Akt signaling pathway to the point of Akt phosphorylation may be necessary but is not, in itself, sufficient to confer protection in our model. Phosphorylation of eNOS was not measured in these studies.
In pig myocardium, the activity of the ERKs increases moderately during brief ischemia and markedly during reperfusion (14). Preischemic application of PD-98059 and U-O126, inhibitors of MAPK kinase (MEK)1/2 and ERK1/2, can block the protective effects of PC on infarct development in some (25, 30) but not all studies (4, 15, 21). Although activation of ERK did not correlate with cardioprotection in our studies, protection of cardiomyocytes during ischemia and reperfusion may be dependent on consequent critical activation of its downstream cascade or cross talk within the cascade. The effector site that may mediate the protective action of ERK in other models is not known.
Multiple downstream targets of both Akt and ERK1/2 that are potentially relevant to cardioprotection have been identified in a wide variety of systems. Activated, phosphorylated Akt stimulates pathways other than p70S6K that are involved in inflammation, cell survival, hypertrophy, and glucose metabolism, including mTOR, BAD, eNOS, GLUT, GSK-3, caspase-9, the Forkhead family of transcription factors, nuclear factor-
B, the stress-activated protein kinase pathway, and Yes-associated protein (19, 29). The activation or lack of activation of each of these pathways in protected, and nonprotected myocardium has not yet been explored.
Several alternate mechanisms for Postcon independent of signaling cascades have been proposed. Although Postcon has been associated with a reduction in the generation of lipid peroxidation products, endothelial dysfunction, and neutrophil accumulation in at-risk myocardium (17, 38), Postcon protected rat neonatal myocyte preparations (31) and buffer-perfused rabbit hearts (36) independent of inflammatory cells, indicating that Postcon exerts a direct effect on the myocyte. Studies using spin-trapping techniques have demonstrated that free radicals are generated in porcine myocardium reperfused after 15 min of regional ischemia (20), possibly through activation of the arachidonate cascade, autoxidation of catecholamines and other compounds, accumulation of reducing equivalents, or mitochondrial respiration (5). Many previous reports have shown that both generation of reactive oxygen species (ROS) and intracellular Ca2+ overload play crucial roles in the induction of cell death during reperfusion and reoxygenation (1, 22), perhaps as stimuli for opening of the mitochondrial permeability transition pore (mPTP) (9, 11). Effective Postcon has been shown to inhibit ROS generated by cardiomyocytes and attenuates cytosolic and mitochondrial Ca2+ accumulation, suggesting a causative link between these events (17). Postcon has also been shown to delay Ca2+-induced mPTP opening (2), although the mechanism of modulation is unknown. Whether Postcon inhibited ROS generation, Ca2+ overload, or mPTP opening in our pig model is unknown.
Modification of the physical environment at the time of reperfusion has long been known to limit the degree of cell death after an ischemic event (24). Although timely reperfusion is critical to salvage myocardium from tissue injury after prolonged ischemia, sudden restoration of blood flow to ischemic myocardium may paradoxically exacerbate some portion of myocytes within ischemic myocardium that were not yet irreversibly damaged. Gradually increasing the perfusion rate and intracoronary pressure during the early minutes of reperfusion may avoid pressure overload and resultant myofibrillar stretching, which would lead to myocardial hypercontracture and myocyte death (26). Alternatively, effective Postcon protocols may improve reflow after an ischemic period, possibly by preventing damage by ROS, thus reducing microvascular reperfusion injury. How these potential mechanisms would have been affected differently by our protocol relative to that used in other species by other laboratories is unclear.
This study is limited by our current understanding of activation of Akt, ERK1/2, and p70S6K and potential cross talk within the signaling cascade and is based on qualitative changes observed in whole tissue extracts. Further studies in pigs are required to more clearly decipher molecular alterations in this pathway that could potentially account for differences in the cardioprotected state evoked by PC and Postcon. Nonetheless, these data indicate that, during the time of reperfusion that is potentially most critical for the salvage of myocardium damaged previously by ischemia, Akt and ERK1/2 signaling pathways are activated by both protocols in this model, but activation does not correlate with cardioprotection.
In summary, our data indicate that Postcon with 30-s cycles of reperfusion and reocclusion does not protect against infarction in an in vivo pig model of ischemia and reperfusion. This inability to confer protection is not explained by limited phosphorylation of Akt and ERK1/2, although ineffective activation of downstream components of these signaling pathways is not discounted. The assessment of intermittent reperfusion as an effective, dependable, and clinically useful method of preventing myocyte injury after ischemia and reperfusion will require a more thorough understanding of the underlying cellular mechanisms that contribute to cardioprotection.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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