Anesth Analg 2006;103:1400-1405
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000240903.63832.d8e
CARDIOVASCULAR ANESTHESIA
Inhibition of Apoptotic Protein p53 Lowers the Threshold of Isoflurane-Induced Cardioprotection During Early Reperfusion in Rabbits
Suneetha Venkatapuram, MD
,
Chen Wang, MD*,
John G. Krolikowski, BA*,
Dorothee Weihrauch, DVM, PhD*,
Judy R. Kersten, MD*
,
David C. Warltier, MD, PhD*
,
Phillip F. Pratt, Jr, PhD*, and
Paul S. Pagel, MD, PhD*
From the *Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), Medical College of Wisconsin and The Clement J. Zablocki Veterans Affairs Medical Center; and Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.
Address correspondence and reprint requests to Paul S. Pagel, MD, PhD, Medical College of Wisconsin, MEB-M4280, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226. Address e-mail to pspagel{at}mcw.edu.
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Abstract
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INTRODUCTION: Exposure to isoflurane before and during early reperfusion protects against myocardial infarction by activating phosphatidylinositol-3-kinase (PI3K)-mediated signaling. The apoptotic protein, p53, is regulated by PI3K, and inhibition of p53 protects against ischemic injury. We tested the hypothesis that p53 inhibition lowers the threshold of isoflurane-induced postconditioning in vivo.
METHODS: Rabbits (n = 73) instrumented for hemodynamic measurement and subjected to a 30-min left anterior descending coronary artery occlusion and 3-h reperfusion received 0.9% saline (control), isoflurane (0.5 or 1.0 minimum alveolar concentration [MAC]) administered for 3 min before and 2 min after reperfusion, the p53 inhibitor pifithrin-
(1.5 or 3.0 mg/kg), or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-. Other rabbits received 3.0 mg/kg pifithrin- or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin- after pretreatment with the selective PI3K inhibitor wortmannin (0.6 mg/kg) or the mitochondrial permeability transition pore opener atractyloside (5 mg/kg).
RESULTS: Isoflurane (1.0 but not 0.5 MAC), pifithrin- (3.0 but not 1.5 mg/kg), and the combination of 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin- significantly (P < 0.05) reduced infarct size (21% ± 4%, 43% ± 7%, 22% ± 4%, 45% ± 4%, and 28% ± 3% [mean ± sd], respectively, of left ventricular area at risk; triphenyltetrazolium chloride staining) when compared with control (45% ± 2%). Atractyloside, but not wortmannin, abolished 3.0 mg/kg pifithrin--induced cardioprotection, whereas atractyloside and wortmannin blocked reductions in infarct size produced by 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-.
CONCLUSION: The results indicate that inhibition of the apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in vivo.
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Introduction
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Brief administration of a volatile anesthetic immediately before or during early reperfusion after prolonged coronary artery occlusion produces protection against myocardial infarction (1–4). The mechanisms responsible for this anesthetic "postconditioning" are incompletely characterized, but activation of the pro-survival phosphatidylinositol-3-kinase (PI3K) signaling cascade seems to play a central role in this process (2,3). Several PI3K-regulated components of this pathway (including 70-kDa ribosomal protein s6 kinase, endothelial nitric oxide synthase, the ß isoform of glycogen synthase kinase [GSK-ß], and the antiapoptotic factor B cell lymphoma protein-2) have been implicated in the cardioprotective effects of volatile anesthetics during reperfusion (5–9). Phosphorylation of many of these enzymes by PI3K may exert protection against ischemic injury via inhibition of mitochondrial permeability transition pore (mPTP) opening during reperfusion (5,7), an action that preserves the function integrity of mitochondrial electron transport while simultaneously preventing the initiation of apoptosis (10,11).
p53 is a tumor suppressor protein known to interact with, and stimulate, the disruption of mitochondria during apoptosis (12). p53 translocates to mitochondria, increases mitochondrial membrane permeability by directly interacting with the apoptotic protein Bax, and causes the loss of mitochondrial membrane potential and the release of cytochrome c (13–15). Direct inhibition of p53 using a selective antagonist or stimulated degradation of the protein by PI3K-mediated phosphorylation of the oncogenic factor murine double minute 2 (Mdm2) protein (16) has been shown to protect against ischemic injury in isolated rat hearts (17). Whether p53 plays a role in isoflurane-induced cardioprotection during reperfusion is unknown. Thus, the current investigation tested the hypothesis that p53 inhibition lowers the threshold for protection against infarction produced by isoflurane during early reperfusion. We also tested the hypothesis that this cardioprotective effect occurs via a mPTP-dependent mechanism in vivo.
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METHODS
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All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of WI. Furthermore, all conformed to the Guiding Principles in the Care and Use of Animals of the American Physiologic Society and were in accordance with the Guide for the Care and Use of Laboratory Animals.
Surgical Instrumentation
Male New Zealand white rabbits weighing between 2.5 and 3.0 kg were anesthetized with IV sodium pentobarbital (30 mg/kg) as previously described (18). Briefly, a tracheostomy was performed through a midline incision, and the lungs of each rabbit were ventilated with positive pressure using an air–oxygen mixture (fractional inspired oxygen concentration = 0.33). Arterial blood gas tensions and acid–base status were maintained within a normal physiological range by adjusting the respiratory rate or tidal volume. Body temperature was maintained with a heating blanket. Heparin-filled catheters were inserted into the right carotid artery and the left jugular vein for measurement of arterial blood pressure and fluid or drug administration, respectively. A thoracotomy was performed at the left fourth intercostal space, and the heart was suspended in a pericardial cradle. A prominent branch of the left anterior descending coronary artery (LAD) was identified, and a silk ligature was placed around this vessel approximately halfway between the base and the apex for the production of coronary artery occlusion and reperfusion. Heparin (500 U) was administered IV immediately before LAD occlusion. Coronary artery occlusion was verified by the presence of epicardial cyanosis and regional dyskinesia in the ischemic zone, and reperfusion was confirmed by observing an epicardial hyperemic response. Hemodynamics were continuously recorded on a polygraph throughout each experiment.
Experimental Protocol
The experimental design is illustrated in Figure 1. Baseline hemodynamics and arterial blood gas tensions were recorded 30 min after instrumentation was completed. All rabbits underwent a 30 min LAD occlusion followed by 3 h of reperfusion. In separate experimental groups, rabbits (n = 7 or 8 per group) were randomly assigned using a Latin square design to receive 0.9% saline (control), isoflurane (0.5 or 1.0 minimum alveolar concentration [MAC]; 1.0 MAC = 2.05% in the rabbit) administered for 3 min before and 2 min after reperfusion, the selective p53 inhibitor pifithrin- (1.5 or 3.0 mg/kg) (19,20), or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-. Additional groups of rabbits received 3.0 mg/kg pifithrin- or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin- in the presence of pretreatment with the selective PI3K inhibitor wortmannin (0.6 mg/kg) or the mPTP opener atractyloside (5 mg/kg). Isoflurane was administered for 3 min before reperfusion to establish a blood concentration of the volatile anesthetic when the coronary blood flow was restored. Pifithrin- and wortmannin were dissolved in dimethylsulfoxide and administered by intraperitoneal and IV injection, respectively, 30 min before coronary occlusion. Atractyloside was dissolved in 2 mL of distilled water and administered over 2 min as an IV infusion 30 min before coronary artery occlusion. We have previously demonstrated that the doses of wortmannin and atractyloside used in the current investigation abolish reductions in infarct size produced by 1.0 MAC isoflurane, but do not alter systemic hemodynamics nor affect myocardial infarct size when administered alone to rabbits (2,5).
Determination of Myocardial Infarct Size
Myocardial infarct size was determined as previously described (21). Briefly, the LAD was reoccluded at the completion of each experiment and 3 mL of patent blue dye was injected IV. The left ventricular (LV) area at risk (AAR) for infarction was separated from surrounding normal areas (stained blue), and the two regions were incubated at 37°C for 20 min in 1% 2,3,5-triphenyltetrazolium chloride in 0.1 M phosphate buffer adjusted to pH 7.4. Infarcted and noninfarcted myocardium within the AAR were carefully separated and weighed after storage overnight in 10% formaldehyde. Myocardial infarct size was expressed as a percentage of the AAR. Rabbits that developed intractable ventricular fibrillation and those with an area at risk <15% of total LV mass were excluded from subsequent analysis.
Statistical Analysis
Statistical analysis of data within and between groups was performed with analysis of variance (ANOVA) for repeated measures followed by the Student–Newman–Keuls test. Changes were considered statistically significant when P < 0.05. All data are expressed as mean ± sd.
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RESULTS
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Seventy-three rabbits were instrumented to obtain 70 successful experiments. Three rabbits were excluded because intractable ventricular fibrillation occurred during or immediately after LAD occlusion (1 control, 1 1.5 mg/kg pifithrin-, 1 wortmannin + 0.5 MAC isoflurane + 1.5 mg/kg pifithrin-). Baseline hemodynamics were similar among groups (Table 1). Coronary artery occlusion significantly (P < 0.05) decreased rate-pressure product in most experimental groups. Decreases in heart rate, mean arterial blood pressure, and rate-pressure product were observed during reperfusion in rabbits receiving isoflurane or pifithrin- alone. A reduction in mean arterial blood pressure and rate-pressure product was observed after 2 min, but not the remainder of reperfusion in rabbits that received the combination of 0.5 MAC isoflurane and 1.5 mg/kg pifithrin-. Rate-pressure product was lower during reperfusion in rabbits receiving wortmannin or atractyloside in the presence or absence of the combination of 0.5 MAC isoflurane and 1.5 mg/kg pifithrin- when compared with control.
Body weight, LV mass, AAR weight, and the ratio of AAR to LV mass were similar among groups (Table 2). Isoflurane (1.0 but not 0.5 MAC) and pifithrin- (3.0 but not 1.5 mg/kg) reduced infarct size (21% ± 4%, 43% ± 7%, 22% ± 4%, and 45% ± 4%, respectively, of the LV AAR) when compared with control (45% ± 2%, Fig. 2). Combined administration of sub-cardioprotective threshold doses of both pifithrin- (1.5 mg/kg) and isoflurane (0.5 MAC) also caused protection (28% ± 3%; P < 0.05 versus control). Wortmannin pretreatment abolished the protection of the combination of pifithrin- (1.5 mg/kg) plus isoflurane (0.5 MAC), but not pifithrin- (3.0 mg/kg) alone (infarct sizes of 45% ± 5% and 24% ± 4% of the LV AAR, respectively). In contrast, atractyloside pretreatment abolished reductions in infarct size produced by the combination of pifithrin- (1.5 mg/kg) plus isoflurane (0.5 MAC) and pifithrin- (3.0 mg/kg) alone (46% ± 2% and 43% ± 4%, respectively).
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DISCUSSION
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The current results confirm previous findings (2,3) demonstrating that brief exposure to 1.0, but not 0.5 MAC isoflurane, immediately before and during early reperfusion, protects against myocardial infarction. The current results further demonstrate that pharmacological inhibition of p53 protects the myocardium against ischemia-reperfusion injury in vivo. The selective p53 inhibitor, pifithrin-, also reduced infarct size in isolated rat hearts exposed to global ischemia and reperfusion (17). Reductions in infarct size produced by pifithrin- were unaffected by wortmannin pretreatment in the current investigation, indicating that p53 inhibition-mediated protection occurs downstream of PI3K. In contrast, decreases in myocardial necrosis produced by pifithrin- alone were abolished by pretreatment with the mPTP opener atractyloside. These findings support previous results (13–15) and suggest that p53 inhibition limits mitochondrial permeability transition from the closed to the open state to produce protection against ischemic injury. To our knowledge, the current results demonstrate for the first time that combined administration of sub-cardioprotective threshold doses of pifithrin- and isoflurane reduce myocardial infarct size in vivo, indicating that p53 inhibition lowers the threshold of isoflurane-induced postconditioning. The beneficial effect of combined sub-cardioprotective threshold doses of pifithrin- and isoflurane was abolished by atractyloside, indicating that the observed decrease in the extent of infarction was mediated by the actions of the selective p53 inhibitor and the volatile anesthetic on mPTP. These data are consistent with our previous results showing that reductions in infarct size produced by the combination of sub-cardioprotective threshold doses of a selective GSK inhibitor and 0.5 MAC isoflurane were also blocked by atractyloside in an identical rabbit model (8).
Apoptosis (programmed cell death) is an adenosine triphosphate-dependent process characterized by selective DNA lysis, apoptotic body formation, condensation of chromatin, a relative lack of inflammation, and preservation of cell membrane structure (22). These features contrast with those of necrosis, in which pronounced cellular damage and intense inflammation are observed. Reperfusion after prolonged coronary artery occlusion stimulates apoptosis and contributes to loss of myocardial integrity (23,24). A central role for inhibition of the apoptotic protein p53 in myocardial and neural protection against injury has been characterized. Activation of p53 by hypoxia or reactive oxygen species (25) produces immediate or delayed programmed cell death by stimulating mitochondrial apoptotic pathways (14) and enhancing transcription of other proapoptotic proteins (e.g., Bax, apoptosis inducing factor). (26) Enhanced p53 expression was observed after ischemia and reperfusion in isolated rat ventricular myocytes, and ischemic preconditioning substantially reduced this effect (27). Ischemic preconditioning also attenuated p53 transcription and translation in hippocampal pyramidal neurons in a rat model of global forebrain ischemia and reperfusion (28). Ischemic preconditioning enhanced Mdm2 phosphorylation and augmented phospho-Mdm2-p53 binding in a PI3K-dependent manner (17). Phosphorylated Mdm2 associates with p53, inactivating the latter protein by blocking its active site and promoting its subsequent degradation through ubiquitin complex formation (29). Thus, ischemic preconditioning may have abrogated the deleterious actions of p53 by PI3K-mediated phosphorylation of the downstream moiety Mdm2 (17). Direct inhibition of p53 using pifithrin- protected against neuronal cell death produced by ischemia, excitotoxins, or amyloid ß-peptide (20). Interestingly, targeted deletion of p53 was recently shown to prevent cardiac rupture after infarction in transgenic mice, presumably by preserving myocardium and mimicking the protective actions of ischemic preconditioning via an inhibition of apoptotic cell death (30). The current results suggest that isoflurane-induced inhibition of p53 may also be responsible for myocardial protection by the volatile anesthetic during early reperfusion in vivo.
Activated GSK-ß binds to and promotes the actions of p53 (31), and data suggest that inhibition of GSK-ß mediates protection against ischemia-reperfusion injury in myocardium (32). For example, selective inhibition of GSK-ß mimicked the beneficial actions of ischemic preconditioning (33) and opioid-induced protection during reperfusion (34). GSK-ß regulated several prosurvival signaling pathways (e.g., PI3K, 70-kDa ribosomal protein s6 kinase, protein kinase C) responsible for cardioprotection against hypoxia-reoxygenation damage in isolated ventricular myocytes (32). Moreover, GSK-ß inhibition limited opening of the mPTP (32). Isoflurane-induced postconditioning was mediated by prevention of mPTP opening through GSK-ß phosphorylation and inactivation (7). Our laboratory recently demonstrated that inhibition of GSK-ß using the selective antagonist SB216763 enhanced isoflurane-induced protection against infarction during early reperfusion via a mPTP-dependent mechanism (8). Thus, these previous results suggest that isoflurane-induced inactivation of GSK-ß may contribute to the inhibition of p53 by the volatile anesthetic observed in the current investigation. This hypothesis is under investigation in our laboratory.
The current results must be interpreted within the constraints of several potential limitations. Previous studies have demonstrated that pifithrin- is a selective inhibitor of p53 (19,20) at the doses used in the current investigation. The relative selectivity of pifithrin- for p53 was also suggested by the observation that reductions in infarct size produced by this drug in the current investigation were unaffected by pretreatment with the PI3K inhibitor wortmannin. Nevertheless, the possibility that pifithrin- may have inhibited other protein kinases involved in myocardial protection cannot be completely excluded from the analysis. We also did not specifically measure the actions of isoflurane or pifithrin- on p53 activity in the current investigation. Dose–response relationships to wortmannin, atractyloside, and p53 were not performed. The larger dose of pifithrin- may also have produced a nonselective action. The route, timing, and duration of administration of wortmannin, atractyloside, and p53 were heterogenous, and these pharmacokinetic factors may have influenced the results. Plasma concentrations of wortmannin, atractyloside, and pifithrin- were also not determined. A previous study demonstrated that ischemic preconditioning activates Mdm2 and enhances phospho-Mdm2-p53 binding in a PI3K-dependent manner (17). Our laboratory has shown that administration of isoflurane-induced postconditioning produces PI3K-dependent phosphorylation of the downstream protein Akt (protein kinase B). (2) Akt has been shown to activate Mdm2 (35) and facilitate Mdm2-mediated ubiquitination and degradation of p53 (29). Thus, it is certainly plausible that isoflurane may also stimulate phosphorylation of Mdm2 and promote the interaction of phospho-Mdm2 with p53 via its actions on Akt, but this hypothesis remains to be examined. Myocardial infarct size is determined primarily by the size of the AAR and extent of coronary collateral perfusion. The AAR expressed as a percentage of total LV mass was similar among groups in the current investigation. Rabbits also have minimal coronary collateral blood flow (36). Thus, it appears unlikely that differences in collateral perfusion among groups account for the observed results. However, coronary collateral blood flow was not specifically quantified in the current investigation. The reductions in myocardial necrosis produced by brief administration of isoflurane during early reperfusion occurred independent of changes in major determinants of myocardial oxygen consumption. Nevertheless, the current results require qualification because coronary venous oxygen tension was not directly measured, and myocardial oxygen consumption was not calculated. Notably, no significant differences in hemodynamics were observed among groups before and during coronary artery occlusion that may account for differences in myocardial infarct size observed among groups.
In summary, the current results confirm that isoflurane protects against myocardial infarction when this volatile anesthetic is briefly administered immediately before and during early reperfusion. The findings further indicate that inhibition of the apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion via a mPTP-dependent mechanism in vivo.
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ACKNOWLEDGMENTS
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The authors thank David A. Schwabe, BSEE (Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin) for technical assistance.
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Footnotes
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Accepted for publication August 2, 2006.
Supported in part by the National Institutes of Health, United States Public Health Service grants HL 054820, HL 063705, GM 008377, and GM 066730.
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Abstract
Introduction
