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CARDIOVASCULAR ANESTHESIA

Inhibition of Glycogen Synthase Kinase Enhances Isoflurane-Induced Protection Against Myocardial Infarction During Early Reperfusion In Vivo

Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), the Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin; 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.

	Abstract

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Inhibition of glycogen synthase kinase (GSK)-ß protects against ischemia-reperfusion injury. Brief exposure to isoflurane before and during early reperfusion after coronary artery occlusion also protects against infarction. Whether GSK-ß mediates this action is unknown. We tested the hypothesis that GSK inhibition enhances isoflurane-induced postconditioning. Rabbits (n = 88; 6 to 7 per group) subjected to a 30-min coronary occlusion followed by 3 h reperfusion received saline, isoflurane (0.5 or 1.0 minimum alveolar concentration [MAC]) administered for 3 min before and 2 min after reperfusion, the selective GSK inhibitor SB216763 (SB21; 0.2 or 0.6 mg/kg), or 0.5 MAC isoflurane plus 0.2 mg/kg SB21. Other groups of rabbits pretreated with phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin (0.6 mg/kg), 70-kDa ribosomal protein s6 kinase (p70s6K) inhibitor rapamycin (0.25 mg/kg), or mitochondrial permeability transition pore (mPTP) opener atractyloside (5 mg/kg) received 0.6 mg/kg SB21 or 0.5 MAC isoflurane plus 0.2 mg/kg SB21. Additional groups received the mPTP inhibitor, cyclosporin A (5 mg/kg), plus 0.2 mg/kg SB21 with or without atractyloside pretreatment. Isoflurane (1.0 but not 0.5 MAC) and SB21 (0.6 but not 0.2 mg/kg) reduced (P < 0.05) infarct size (21% ± 5%, 44% ± 7%, 23% ± 4%, and 46% ± 2%, respectively, of left ventricular area at risk, mean± sd; triphenyltetrazolium staining) as compared with control (42% ± 6%). Isoflurane (0.5 MAC) plus 0.2 mg/kg SB21 and cyclosporin A plus 0.2 mg/kg SB21 produced similar degrees of protection (24% ± 4% and 27% ± 6%, respectively). Atractyloside but not wortmannin or rapamycin abolished protection produced by 0.6 mg/kg SB21 and 0.5 MAC isoflurane plus 0.2 mg/kg SB21. Thus, GSK inhibition enhances isoflurane-induced protection against infarction during early reperfusion via a mPTP-dependent mechanism.

	Introduction

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Glycogen synthase kinase (GSK) is an important regulator of cellular function (1). Activation of the ß isoform of GSK has been implicated in several diseases, including diabetes mellitus (2), obesity (2), and Alzheimer's (3). Data suggest that inhibition of GSK-ß may play a critical role in myocardial protection against ischemia-reperfusion injury. Selective inhibition of GSK-ß mimicked the beneficial actions of ischemic preconditioning (4) and opioid-induced myocardial protection during reperfusion (5). GSK-ß was further shown to integrate and control several pro-survival signaling pathways, including phosphatidylinositol-3-kinase (PI3K), target of rapamycin 70-kDa ribosomal protein s6 kinase (TOR/p70s6K), protein kinase C, and protein kinase A, during myocardial protection against hypoxia-reoxygenation in isolated ventricular myocytes (6). Moreover, GSK-ß inhibition limited opening of the mitochondrial permeability transition pore (mPTP) (6), a putative end-effector that may be responsible for protection against ischemic damage (7–9). These latter data provided compelling evidence that many endogenous signaling pathways converge upon and regulate the activity of GSK-ß, thereby favorably modulating mitochondrial permeability transition and producing protection (10).

Volatile anesthetics exert important cardioprotective effects when administered immediately before and during early reperfusion (11–13). The precise timing of coronary artery occlusion is unknown in the majority of patients with acute myocardial infarction, and the ability to provide an effective therapeutic intervention immediately before or during early reperfusion may be clinically advantageous. Our laboratory has previously demonstrated that reductions in myocardial infarct size produced by brief exposure to isoflurane (ISO) immediately before and during early reperfusion are mediated by activation of PI3K, extracellular regulated kinases 1 and 2, p70s6K, and endothelial nitric oxide synthase and by inhibition of mPTP in a mitochondrial adenosine triphosphate-regulated potassium channel-dependent manner (13–16). Whether GSK plays a role in this ISO-induced myocardial protection during reperfusion is unknown. Thus, the current investigation tested the hypothesis that inhibition of GSK enhances myocardial protection against infarction produced by ISO during early reperfusion. We also tested the hypothesis that this cardioprotective effect occurs via a mPTP-dependent mechanism in vivo.

	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 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 additional doses of pentobarbital were titrated as required to assure that pedal and palpebral reflexes were absent throughout the experiment as previously described (17). Briefly, a tracheostomy was performed through a midline incision, and each rabbit's lungs were ventilated with positive pressure using an air-oxygen mixture (fractional inspired oxygen concentration = 0.33). 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. IV heparin (500 U) was administered 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. Hemodynamic data were continuously recorded on a polygraph throughout each experiment.

The experimental design is illustrated in Figure 1. Baseline hemodynamic data 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 = 6 to 7 per group) were randomly assigned (using a Latin square design) to receive 0.9% saline (control), ISO (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 GSK inhibitor SB216763 (SB21; 0.2 or 0.6 mg/kg), or the combination of 0.5 MAC ISO and 0.2 mg/kg SB21. Additional experimental groups received 0.6 mg/kg SB21 or 0.5 MAC ISO plus 0.2 mg/kg SB21 in the presence of pretreatment with the selective PI3K inhibitor wortmannin (0.6 mg/kg), the selective p70s6K inhibitor rapamycin (RAP) (0.25 mg/kg) or the mPTP opener atractyloside (ATR) (5 mg/kg). Two final groups received the combination of the selective mPTP inhibitor cyclosporin A (CsA) (5 mg/kg) and 0.2 mg/kg SB21 in the presence or absence of ATR. ISO was administered for 3 min before reperfusion to establish a blood concentration of the volatile anesthetic when the coronary blood flow was restored. SB21 was dissolved in dimethylsulfoxide and administered over 2 min as an IV infusion 5 min before reperfusion. RAP was dissolved in dimethylsulfoxide and administered IV 10 min before reperfusion. ATR was dissolved in 2 mL of distilled water and administered over 2 min as an IV infusion 30 min before coronary artery occlusion. CsA 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. We have previously demonstrated that the doses of wortmannin, RAP, and ATR used in the current investigation abolish reductions in infarct size produced by 1.0 MAC ISO but do not alter systemic hemodynamics nor affect myocardial infarct size when administered alone to rabbits (13–16). In addition, the dose (5 mg/kg) of CsA used in the current investigation does not affect infarct size nor does it produce other hemodynamic effects when administered alone in an identical experimental model (15). However, the combination of this subthreshold dose of CsA and 0.5 MAC ISO reduced myocardial infarct size to a degree equivalent to that produced by 1.0 MAC ISO or ischemic postconditioning (13,15).

View larger version (16K): [in this window] [in a new window]   Figure 1. Schematic illustration depicting the experimental protocol. ISO = isoflurane; SB21 = SB216763.

Myocardial infarct size was measured as previously described (18). 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 2 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 AAR <15% of total LV mass were excluded from subsequent analysis.

Statistical analysis of data within and among groups was performed with analysis of variance for repeated measures followed by the Student-Newman-Keuls test (19). Changes were considered statistically significant when P < 0.05. All data are expressed as mean ± sd.

	Results

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Ninety-five rabbits were instrumented to obtain 88 successful experiments. Two rabbits were excluded because of technical problems during instrumentation. Five rabbits were excluded because intractable ventricular fibrillation occurred during or immediately after LAD occlusion (one 0.5 MAC ISO plus 0.2 mg/kg SB21 plus wortmannin; one 1.0 MAC ISO plus RAP; one 0.6 mg/kg SB21 plus ATR; two 0.2 mg/kg SB21 plus 5 mg/kg CsA plus ATR). Baseline hemodynamic data were similar among groups, but a few significant (P < 0.05) differences were observed (Table 1). The mean arterial blood pressures in the ISO (0.5 MAC) + SB21 (0.2 mg/kg) + RAP, CsA + SB21 (0.2 mg/kg), and CsA + SB21 (0.2 mg/kg) + ATR groups were significantly <1.0 MAC ISO alone but not different from control under baseline conditions. In addition, the rate-pressure product in the SB21 (0.6 mg/kg) + RAP group was also significantly less that observed in the 1.0 MAC ISO group but not control during coronary artery occlusion. However, no differences in rate-pressure product were observed among groups under baseline conditions. Coronary artery occlusion significantly 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.

Body weight, LV mass, AAR weight, and the ratio of AAR to LV mass were similar among groups (Table 2). Brief exposure to ISO (1.0 but not 0.5 MAC) significantly (P < 0.05) reduced infarct size (21% ± 5% and 44% ± 7% of LV AAR, respectively) as compared with control (42% ± 6%). SB21 (0.6 but not 0.2 mg/kg) also reduced infarct size (23% ± 4% and 46% ± 2%, respectively; Fig. 2). The combination of 0.5 MAC ISO and 0.2 mg/kg SB21 protected against infarction (24% ± 4%). ATR but not wortmannin or RAP abolished the protection produced by 0.6 mg/kg SB21 (42% ± 5%, 27% ± 8%, and 22% ± 4%, respectively) and the combination of 0.5 MAC ISO and 0.2 mg/kg SB21 (45% ± 4%, 23% ± 3%, and 22% ± 3%, respectively). The combination of 5 mg/kg CsA and 0.2 mg/kg SB21 reduced infarct size (27% ± 6%), and this protective effect was also inhibited by ATR (44% ± 3%).

View larger version (30K): [in this window] [in a new window]   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), SB216763 (SB21, 0.2 or 0.6 mg/kg), 0.5 MAC ISO plus 0.2 mg/kg SB21, or cyclosporin A (CsA, 5 mg/kg) plus 0.2 mg/kg SB21 (top panel). Infarct sizes in rabbits receiving 0.6 mg/kg SB21 or 0.5 MAC ISO plus 0.2 mg/kg SB21 in the presence of wortmannin (WOR, 0.6 mg/kg), rapamycin (RAP, 0.25 mg/kg), or atractyloside (ATR, 5 mg/kg) are depicted in the bottom panel. Infarct sizes in rabbits receiving cyclosporin A (CsA, 5 mg/kg) plus 0.2 mg/kg SB21 in the presence of ATR pretreatment are also illustrated 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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The current results indicate that SB21, a selective inhibitor of GSK (20), produces myocardial protection when administered shortly before reperfusion in rabbits, confirming previous findings in rats (5). Reductions in infarct size produced by SB21 were unaffected by pretreatment with wortmannin and RAP. These findings also concur with the previous results (5) and indicate that the GSK inhibition-mediated myocardial protection occurs downstream of both PI3K and p70s6K (6,21). In contrast, decreases in myocardial necrosis produced by SB21 alone or by the combination of subthreshold doses of SB21 and the mPTP inhibitor, CsA, were abolished by pretreatment with the mPTP opener, ATR. These findings provide further pharmacological evidence in support of previous results (6) indicating that GSK inhibition limits mitochondrial permeability transition from the closed to the open state to produce protection against ischemic injury. The current results confirm our previous findings (13–15) demonstrating that brief exposure to 1.0 but not 0.5 MAC ISO immediately before and during early reperfusion protects against myocardial infarction. To our knowledge, the results demonstrate for the first time that inhibition of GSK activity enhances ISO-induced protection against infarction. These beneficial effects were abolished by pretreatment with atractyloside, indicating that the observed decrease in the extent of infarction was mediated by the combined actions of the selective GSK inhibitor and the volatile anesthetic on mPTP. These data are consistent with our previous findings showing that inhibition of mPTP with CsA enhances whereas opening with ATR abolishes ISO-induced myocardial protection during early reperfusion (15). In contrast, the protection against infarction produced by subthreshold doses of SB21 and ISO was unaffected by pretreatment with wortmannin and RAP. We have previously demonstrated that myocardial protection by 1.0 MAC ISO during early reperfusion is mediated by activation of PI3K and p70s6K in rabbits because selective inhibitors of these enzymes blocked reductions in infarct size produced by the volatile anesthetic (13,16). Thus, the data provide pharmacological evidence that ISO produces a direct inhibitory effect on GSK independent of its actions on PI3K and p70s6K activity.

Opening of the mPTP may occur specifically at the onset of reperfusion (22). Cell death has been postulated to rapidly ensue as a result of elimination of the mitochondrial membrane potential and subsequent inhibition of oxidative phosphorylation (23). Inhibition of mPTP has been shown to mediate the protective effects of ischemic and volatile anesthetic preconditioning and postconditioning (7,9,15,24). The mechanisms by which inhibition of GSK favorably affects mitochondrial permeability transition to cause protection against ischemia-reperfusion injury are unclear. Activated GSK-ß binds to and promotes the actions of p53 (25), a tumor suppressor protein known to interact with and stimulate the disruption of mitochondria during apoptosis (26). p53 translocates to mitochondria, induces mitochondrial membrane permeability, and causes the loss of the membrane potential and the release of cytochrome c (27,28). Inhibition of p53 using the selective antagonist pifithrin or down-regulation of the protein by PI3K-mediated phosphorylation of murine double minute 2 (Mdm2; an oncogenic factor known to facilitate p53 degradation) (29) have been shown to protect against ischemic injury in isolated rat hearts (30). The precise role of p53 in the interaction between GSK-ß and mPTP during cardioprotective processes, including ISO-induced postconditioning, remains to be defined and represents an active area of research in our laboratory. ISO also enhanced expression of B cell lymphoma-2 (Bcl-2), another potentially important regulator of mPTP, and reduced cytochrome c translocation from mitochondria in isolated atrial and ventricular myocytes subjected to simulated reperfusion injury in vitro (31). The beneficial actions of ISO on mitochondrial integrity (e.g., cytochrome c release) (32) observed in these experiments were abolished by pretreatment with a selective Bcl-2 inhibitor (31). Bcl-2 is an antiapoptotic protein located in the outer mitochondrial membrane (33), and an interaction between this protein and mPTP inhibition was shown during delayed ischemic preconditioning (34). Thus, ISO-induced protection against infarction during early reperfusion may also be mediated by the combined actions of the volatile anesthetic on Bcl-2 and GSK-ß. We are currently conducting experiments designed to test this hypothesis.

The current results must be interpreted within the constraints of several potential limitations. Previous studies have indicated that SB21 is a selective inhibitor of GSK that does not affect the activity of PI3K, p70s6K, mitogen-activated protein kinases, or phosphoinositide-dependent kinase 1 (20). SB21 also mimicked the protective effects of opioid agonists administered immediately before reperfusion (5). In addition, the relative selectivity of SB21 for GSK was demonstrated in the current investigation by observation that reductions in infarct size produced by this drug were not inhibited by pretreatment with the PI3K and p70s6K inhibitors wortmannin and RAP, respectively. Nevertheless, the possibility that this drug may have inhibited other protein kinases involved in myocardial protection cannot be completely excluded from the analysis. We did not biochemically identify the GSK isoform ( or ß), define the specific residue of the enzyme involved in ISO-induced postconditioning, or measure the GSK activity in vitro. However, previous studies have strongly implicated phosphorylation of the N-terminal Ser (9) residue of GSK-ß in the inhibition of this enzyme during ischemic preconditioning (4) and opioid-induced myocardial protection during reperfusion (5). GSK-ß, but not –, was also shown to be localized to mitochondria (26). Thus, it appears highly likely that GSK-ß mediates myocardial protection produced by ISO during early reperfusion as well. In fact, a very recent study demonstrated that ISO-induced postconditioning was mediated by prevention of mPTP opening through GSK-ß phosphorylation and inactivation (35).

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 (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 ISO 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, the differences in hemodynamics among groups before and during coronary artery occlusion were not responsible for the differences observed in myocardial infarct size. Finally, the current results require qualification because aging has recently been shown to modulate myocardial protection (37) and we did not specifically use rabbits from a preselected age range. Nevertheless, rabbits of similar body weight were used in the current investigation.

In summary, the current investigation confirms that ISO protects against myocardial infarction when this volatile anesthetic is briefly administered immediately before and during early reperfusion. The findings further indicate that inhibition of GSK enhanced the protective effect of ISO-induced postconditioning via a mPTP-dependent mechanism in vivo.

The authors thank David A. Schwabe BSEE (Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin) for technical assistance and Mary Lorence-Hanke AA (Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin) for assistance in preparation of the manuscript.

	Footnotes

 
Accepted for publication December 6, 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).

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				C. Wang, D. A. Neff, J. G. Krolikowski, D. Weihrauch, M. Bienengraeber, D. C. Warltier, J. R. Kersten, and P. S. Pagel The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesth. Analg., May 1, 2006; 102(5): 1355 - 1360. [Abstract] [Full Text] [PDF]

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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