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Anesth Analg 2006;102:1355-1360
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000202463.28618.64

CARDIOVASCULAR ANESTHESIA

The Influence of B-Cell Lymphoma 2 Protein, an Antiapoptotic Regulator of Mitochondrial Permeability Transition, on Isoflurane-Induced and Ischemic Postconditioning in Rabbits

Chen Wang, MD, Donald A. Neff, BS, John G. Krolikowski, BA, Dorothee Weihrauch, DVM, PhD, Martin Bienengraeber, PhD, David C. Warltier, MD, PhD, Judy R. Kersten, MD, and Paul S. Pagel, MD, PhD

Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), the Medical College of Wisconsin; the Clement J. Zablocki Veterans Affairs Medical Center; 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, WI 53226. Address e-mail to pspagel{at}mcw.edu.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Brief exposure to isoflurane or repetitive, transient ischemia during early reperfusion after prolonged coronary artery occlusion protects against myocardial infarction by inhibiting the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP during delayed ischemic preconditioning occurred concomitant with enhanced expression of the antiapoptotic protein B cell lymphoma-2 (Bcl-2). We tested the hypothesis that Bcl-2 mediates myocardial protection by isoflurane or brief ischemic episodes during reperfusion in rabbits (n = 91) subjected to a 30-min left anterior descending coronary artery occlusion followed by 3 h reperfusion. Rabbits received 0.9% saline, isoflurane (0.5 or 1.0 minimum alveolar concentration, MAC) administered for 3 min before and 2 min after reperfusion, 3 cycles of postconditioning ischemia (10 or 20 s each) during early reperfusion, 0.5 MAC isoflurane plus 3 cycles of postconditioning ischemia (10 s), or the direct mPTP inhibitor cyclosporin A (CsA, 10 mg/kg) in the presence or absence of the selective Bcl-2 inhibitor HA14-1 (2 mg/kg, i.p.). Isoflurane (1.0, but not 0.5, MAC) and postconditioning ischemia (20 s but not 10 s) significantly (P < 0.05) reduced infarct size (mean ± sd, 21% ± 4%, 43% ± 7%, 19% ± 7%, and 39% ± 11%, respectively, of left ventricular area at risk) as compared with control (44% ± 4%). Isoflurane (0.5 MAC) plus 10 s postconditioning ischemia and CsA alone also exerted protection. HA14-1 alone did not affect infarct size nor block protection produced by CsA but abolished reductions in infarct size caused by 1.0 MAC isoflurane, 20 s postconditioning ischemia, and 0.5 MAC isoflurane plus 10 s postconditioning ischemia. The results suggest that Bcl-2 mediates isoflurane-induced and ischemic postconditioning by indirectly modulating mPTP activity in vivo.


   Introduction
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 Abstract
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Methods
 Results
 Discussion
 References
 
The precise onset of coronary artery occlusion cannot be predicted in most patients with acute myocardial infarction. This has substantially limited the use of ischemic or pharmacological preconditioning as a clinical strategy to preserve susceptible myocardium in these patients. Experimental data suggest that brief, repetitive myocardial ischemic stimuli (1–4) or a variety of drugs—including bradykinin (5), adenosine receptor agonists (5), insulin (6), statins (7), opioids (8), and volatile anesthetics (4,9–13)—conducted or administered, respectively, immediately before or during early reperfusion after prolonged coronary artery occlusion also protect against infarction. This "postconditioning" process causes myocardial protection that is equivalent to that afforded by preconditioning and may be advantageous because prior knowledge of the onset of ischemia is not required. This concept was emphasized by a recent report demonstrating that ischemic postconditioning conducted during coronary angioplasty provides substantial myocardial protection in patients with acute myocardial infarction (14).

We and others (4,10–13) recently demonstrated that reductions in myocardial infarct size produced by brief exposure to isoflurane immediately before and during early reperfusion are mediated by activation of the pro-survival phosphatidylinositol-3-kinase (PI3K)-mediated signaling pathway that converges upon and inhibits opening of the mitochondrial permeability transition pore (mPTP). We have also shown that inhibition of apoptosis (programmed cell death) contributes to reductions in infarct size produced by isoflurane under these conditions (10). B cell lymphoma-2 (Bcl-2) protein has been identified in the outer mitochondrial membrane (15), is known to regulate the activity of mPTP (16,17), and has been shown to inhibit apoptosis (18). Over-expression of Bcl-2 attenuated apoptosis and protected against ischemia-reperfusion injury in transgenic mice (19). A key interaction between Bcl-2 and mPTP inhibition was previously implicated during delayed ischemic preconditioning (20). A selective inhibitor of Bcl-2 also attenuated isoflurane-induced reductions in apoptosis in isolated atrial and ventricular myocytes subjected to hypoxia-reoxygenation injury (21). Whether Bcl-2 mediates the protective effects of volatile anesthetic-induced or ischemic postconditioning is unknown. Thus, the current investigation tested the hypothesis that Bcl-2 mediates myocardial protection produced by brief exposure to isoflurane or transient, repetitive ischemic episodes before and during early reperfusion after prolonged coronary artery occlusion.


   Methods
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 Methods
Results
 Discussion
 References
 
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 Wisconsin. 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.

Male New Zealand white rabbits weighing between 2.5 and 3.0 kg were anesthetized with IV sodium pentobarbital (30 mg/kg) and acutely instrumented for the measurement of systemic hemodynamics as previously described (4,10–12). 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 occlusion of the left anterior descending coronary artery (LAD) followed by 3 h of reperfusion. Briefly, a left thoracotomy was performed at the fourth intercostal space, and the heart was suspended in a pericardial cradle. A prominent branch of the LAD was identified, and a silk ligature was placed around this vessel approximately halfway between the base and apex for the production of coronary artery occlusion and reperfusion. Each rabbit was anticoagulated with 500 U of heparin 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. In separate experimental groups, rabbits (n = 7 or 8 per group) were randomly assigned 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, 3 cycles of postconditioning ischemia (10 s or 20 s each) during early reperfusion, 0.5 MAC isoflurane plus 3 cycles of postconditioning ischemia (10 s), or the direct mPTP inhibitor cyclosporin A (10 mg/kg) in the presence or absence of the selective Bcl-2 inhibitor HA14-1 (22). Isoflurane was administered for 3 min before reperfusion to establish a blood concentration of the volatile anesthetic when the coronary blood flow was restored. Postconditioning ischemia consisted of 3 cycles of 10 s or 20 s coronary occlusions separated by 10 s or 20 s reperfusions beginning 10 s or 20 s after initiation of reperfusion, respectively (4). HA14-1 (2 mg/kg; Sigma-Aldrich, St. Louis, MO) was dissolved in dimethylsulfoxide (0.3 mL) and administered by intraperitoneal injection 30 min before coronary occlusion. Cyclosporin A (A. G. Scientific, San Diego, CA) was dissolved in 2 mL of a 50% ethanol-polyethylene glycol mixture and administered over 2 min as an IV infusion 5 min before reperfusion. Myocardial infarct size was measured using triphenyltetrazolium chloride staining and was expressed as a percentage of the left ventricular (LV) area at risk (AAR) (23). Rabbits that developed intractable ventricular fibrillation and those with an AAR <15% of total LV mass were excluded from subsequent analysis.


Figure 110
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  		Figure 1. Schematic illustration depicting the experimental protocol.

 

Statistical analysis of data within and between groups was performed with analysis of variance 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.


   Results
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 Methods
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Discussion
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Ninety-seven rabbits were instrumented to obtain 91 successful experiments. Two rabbits were excluded because of technical problems during instrumentation. Four rabbits were excluded because intractable ventricular fibrillation occurred during or after LAD occlusion (1 HA14-1 alone; 3 HA14-1 plus cyclosporin A). Baseline hemodynamic values 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 many experimental groups.


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  		Table 1. Hemodynamics

 

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 postconditioning ischemia (20 s but not 10 s) reduced infarct size (21% ± 4%, 43% ± 7%, 19% ± 7%, and 39% ± 11%, respectively, of AAR) as compared with control (44% ± 4%) (Fig. 2). Isoflurane (0.5 MAC) plus 10 s postconditioning ischemia and cyclosporin A also exerted protection (20% ± 14% and 25% ± 3%, respectively). HA14-1 alone did not affect infarct size (42% ± 2%) nor block protection produced by cyclosporin A (24% ± 2%), but this drug abolished reductions in infarct size caused by 1.0 MAC isoflurane (38% ± 8%), 20 s postconditioning ischemia (46% ± 3%), and 0.5 MAC isoflurane plus 10 s postconditioning ischemia (43% ± 4%).


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  		Table 2. Left Ventricular Area at Risk

 

Figure 210
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  		Figure 2. Myocardial infarct size depicted as a percentage of the left ventricular area at risk in rabbits receiving 0.9% saline (control, CON), isoflurane (ISO, 0.5 or 1.0 MAC), three cycles of postconditioning ischemia (POST, 10 or 20 s), 0.5 MAC ISO plus 10 s POST, or cyclosporin A (CsA, 10 mg/kg) are illustrated in the top panel. Infarct sizes in rabbits receiving 0.9% saline, 1.0 MAC ISO, 20 s POST, 0.5 MAC ISO plus 10 s POST, or CsA (10 mg/kg) in the presence of pretreatment with the selective Bcl-2 antagonist HA14-1 (2 mg/kg, intraperitoneal) are depicted in the bottom panel. Each point represents a single experiment. All data are mean± sd *Significantly (P < 0.05) different from CON.

 


   Discussion
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 Methods
 Results
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References
 
The current results confirm our previous findings (4) demonstrating that brief exposure to isoflurane (1.0 but not 0.5 MAC) or postconditioning ischemia (20 s but not 10 s) during early reperfusion protects against myocardial infarction. The findings also verify that a subthreshold postconditioning ischemic stimulus (10 s) enhances isoflurane-induced myocardial protection during early reperfusion (4). The results demonstrate for the first time that inhibition of Bcl-2 activity using the selective antagonist HA14-1 abolishes protection against infarction produced by isoflurane, repetitive, brief ischemic episodes, or their combination in vivo. Interestingly, HA14-1 did not affect reductions in infarct size produced by the direct mPTP inhibitor cyclosporin A. These data suggest that the protective effects of isoflurane, transient, repetitive ischemia, or their combination occur as a result of indirect modulation of mPTP mediated "upstream" by Bcl-2. This protein has been shown to be an important regulator of apoptotic cell death (24), which, along with necrosis, contributes to infarct size (25,26). The current results with isoflurane are supported by recent findings indicating that isoflurane protects atrial and ventricular myocytes against apoptosis (as indicated by cytochrome c release and TUNEL-positive cell count) produced by hypoxia-reoxygenation or oxidative stress in part by increasing Bcl-2 expression (21). The beneficial effects of isoflurane on apoptosis were also inhibited by HA14-1, indicating that Bcl-2 mediated the protective effects of the volatile anesthetic in this model as well (21). Together with these previous findings, the current results provide compelling evidence to support the hypothesis that the anti-apoptotic protein Bcl-2 is a critical mediator of isoflurane-induced postconditioning in vivo.

An important role for mPTP inhibition in isoflurane-induced reductions in infarct size during early reperfusion has been previously demonstrated (11,13). Opening of mPTP occurs specifically at the onset of reperfusion (27), abolishes the mitochondrial membrane potential, inhibits oxidative phosphorylation, and facilitates the release or activation of proapoptotic proteins including cytochrome c (28). These actions rapidly produce cell death. Several proteins, including Bcl-2, regulate mitochondrial permeability transition (24). Closure of mPTP enhanced, whereas opening abolished, isoflurane-induced postconditioning in a mitochondrial KATP channel-dependent manner (11). PI3K-Akt (protein kinase B) has been shown to phosphorylate and activate Bcl-2 concomitant with inactivation of pro-apoptotic proteins including Bad, Bax, Bim, and p53 (24). Brief exposure to isoflurane immediately before and during early reperfusion phosphorylated Akt in a PI3K-dependent manner in vivo (4). Thus, inhibition of mPTP opening by isoflurane may occur as a result of PI3K-mediated increases in Bcl-2 activity. Another research group also recently reported that prevention of mPTP opening facilitates isoflurane-induced myocardial protection during reperfusion in rats (13). These beneficial actions occurred concomitant with phosphorylation of the ß isoform of glycogen synthase kinase (GSK) (13). Many prosurvival signaling pathways (e.g., PI3K, target of rapamycin 70-kDa ribosomal protein s6 kinase, protein kinase C) converge on GSK-ß, and this protein has been shown to be another critical modulator of mPTP activity (29). We recently reported that a selective GSK inhibitor enhances myocardial protection against infarction by isoflurane during early reperfusion by a mPTP-dependent mechanism (30). Thus, the current and previous data suggest that isoflurane-induced postconditioning may be mediated by both Bcl-2 and GSK-ß via their actions on mPTP.

Previous investigations have also implicated Bcl-2 in protection against ischemia-reperfusion injury. Bcl-2 attenuates ischemic and other forms of cellular injury by inhibiting cytochrome c translocation (31) and preventing deleterious calcium release from the endoplasmic reticulum (32). Ischemic preconditioning reduced apoptosis by enhancing Bcl-2 expression in isolated rat hearts (33,34). Hypothermia-induced reductions in ischemia-reperfusion injury were also associated with increased Bcl-2 expression (35). Furthermore, over-expression of Bcl-2 in transgenic mice prevented apoptosis and produced myocardial protection against ischemic injury (19). A critical interaction between Bcl-2 and mPTP has been previously suggested, as myocardial protection produced by delayed ischemic preconditioning was also associated with inhibition of mPTP, reduced mitochondrial swelling and enhanced Bcl-2 expression (20). In addition, a central role for mPTP in ischemic postconditioning has been previously demonstrated (36–38). The current results support these findings and indicate that reductions in infarct size produced by repetitive, brief ischemic episodes during early reperfusion are blocked by the selective Bcl-2 inhibitor HA14-1. Thus, the data suggest that Bcl-2 mediates the beneficial effects of ischemic postconditioning in vivo, most likely through salutary modulation of mPTP activity.

The current results must be interpreted within the constraints of several potential limitations. HA14-1 has been shown to be a selective inhibitor of Bcl-2 in tumor cells (22), but the possibility that this drug may have inhibited other protein kinases involved in myocardial protection when used in the rabbit cannot be completely excluded from the analysis. We did not specifically identify the impact of isoflurane, transient, repetitive ischemia, or their combination on Bcl-2 expression in the current investigation. However, previous studies have reported that isoflurane increases Bcl-2 expression in isolated cardiac myocytes exposed to hypoxia-reoxygenation (21). Furthermore, Bcl-2 expression was enhanced during delayed ischemic preconditioning concomitant with closure of the mPTP (20). Thus, it appears highly likely that Bcl-2 also mediates myocardial protection produced by brief exposure to isoflurane or transient, repetitive ischemic episodes during early reperfusion as well. 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 have also been shown to possess little if any coronary collateral blood flow (39). 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, transient, repetitive ischemia, or their combination 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 in the current investigation.

In summary, the current results indicate that inhibition of Bcl-2 activity abolishes the protective effects against myocardial infarction produced by brief exposure to isoflurane, transient, repetitive ischemic episodes, or their combination during early reperfusion after prolonged coronary artery occlusion in barbiturate-anesthetized, acutely instrumented rabbits. The data further suggest that the isoflurane-induced and ischemic postconditioning occur as a result of indirect modulation of mPTP mediated upstream by Bcl-2 in vivo.

The authors thank David A. Schwabe BSEE (Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin) for technical assistance.


   Footnotes
 
Accepted for publication December 12, 2005.

Supported, in part, by American Heart Association Greater Midwest Affiliate grant AHA 0265259Z (to Dr. Weihrauch) and National Institutes of Health grants HL 054820 (to Dr. Warltier), GM 008377 (to Dr. Warltier), GM 066730 (to Dr. Warltier), and HL 063705 (to Dr. Kersten) from the United States Public Health Service (Bethesda, MD).


   References
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 Abstract
 Introduction
 Methods
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 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press