The second window of desflurane-induced preconditioning is mediated by STAT3: role of Pim-1 kinase

• Published in: Acta anaesthesiologica Scandinavica Vol. 60; no. 1; pp. 103 - 116
• Main Authors: Stumpner, J., Tischer-Zeitz, T., Lotz, C., Umminger, J., Neuwirth, A., Smul, T. M., Redel, A., Kehl, F., Roewer, N., Lange, M.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-01-2016; Wiley Subscription Services, Inc
• Subjects: Anesthetics, Inhalation - pharmacology; Animals; bcl-Associated Death Protein - metabolism; Blood Pressure; Cardiomyocytes; Coronary artery; Data processing; Enzyme inhibitors; Heart Rate; Inhibitors; Ischemia; Ischemic Preconditioning, Myocardial; Isoflurane - analogs & derivatives; Isoflurane - pharmacology; Janus kinase; Male; Mice; Mice, Inbred C57BL; Myocardial infarction; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion; Nuclear transport; Occlusion; Pentobarbital; Powder injection molding; Preconditioning; Proto-Oncogene Proteins c-pim-1 - drug effects; Proto-Oncogene Proteins c-pim-1 - metabolism; Reperfusion; Rodents; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - drug effects; STAT3 Transcription Factor - metabolism; Translocation; Triphenyltetrazolium chloride; Tyrphostins - pharmacology; Variance analysis
• ISSN: 0001-5172; 1399-6576
• DOI: 10.1111/aas.12587

Background
Late ischemic preconditioning is mediated via nuclear transcription factor signal transducer and activator of transcription 3 (STAT3). Pim‐1 kinase reduces infarct size in cardiomyocytes and is regulated by STAT3. We tested the hypothesis that late desflurane‐induced preconditioning (DES‐SWOP) is mediated via STAT3 and Pim‐1.
Methods
After institutional approval, pentobarbital‐anesthetized male C57BL/6 mice were subjected to 45 min coronary artery occlusion (CAO) and 3 h reperfusion. Control animals received no additional intervention. Desflurane was administered 48 h before CAO either alone or in combination with the janus kinase/STAT3 inhibitor AG‐490 (40 μg/g i.p., 20 min before desflurane administration) or the Pim‐1 kinase inhibitor II (PIM‐Inh.II, 10 μg/g i.p., 15 min before CAO). Infarct size (IS) and area at risk were determined with triphenyltetrazolium chloride and Evans blue, respectively. Additionally, cytosolic and nuclear fractions were separated at two different time points and expression of STAT3, phospho‐STAT3Ser727, phospho‐STAT3Tyr705, Pim‐1, Bad and phospho‐BadSer112 were determined by Western Blot analysis. Data were analyzed with one‐way or two‐way ANOVA and post hoc Duncan test and are presented as mean ± SEM.
Results
IS was 47 ± 2% (n = 7–8 per group) in control animals (CON). DES‐SWOP reduced myocardial infarct size to 23 ± 4%* (*P < 0.05 vs. CON). AG‐490 alone did not affect myocardial infarct size (44 ± 7%), but abolished DES‐SWOP (44 ± 4%). Blockade of Pim‐1 did not affect the protection by DES‐SWOP (34 ± 4%*). Desflurane reduced cytosolic content and enhanced nuclear content of phospho‐STATSer727. After 48 h, desflurane enhanced Pim‐1 activity, whereas Pim‐1 expression remained unchanged.
Conclusion
These data suggest that DES‐SWOP is mediated by activation and nuclear translocation of STAT3. The impact of Pim‐1 in DES‐SWOP signaling remains unclear.