Skip to main content
Log in

Attenuation of ischemia–reperfusion injury by sevoflurane postconditioning involves protein kinase B and glycogen synthase kinase 3 beta activation in isolated rat hearts

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Volatile anesthetic ischemic postconditioning reduces infarct size following ischemia/reperfusion. Whether phosphorylation of protein kinase B (PKB/Akt) and glycogen synthase kinase 3 beta (GSK3β) is causal for cardioprotection by postconditioning is controversial. We therefore investigated the impact of PKB/Akt and GSK3β in isolated perfused rat hearts subjected to 40 min of ischemia followed by 1 h of reperfusion. 2.0% sevoflurane (1.0 minimum alveolar concentration) was administered at the onset of reperfusion in 15 min as postconditioning. Western blot analysis was used to determine phosphorylation of PKB/Akt and its downstream target GSK3β after 1 h of reperfusion. Mitochondrial and cytosolic content of cytochrome C checked by western blot served as a marker for mitochondrial permeability transition pore opening. Sevoflurane postconditioning significantly improved functional cardiac recovery and decreased infarct size in isolated rat hearts. Compared with unprotected hearts, sevoflurane postconditioning-induced phosphorylation of PKB/Akt and GSK3β were significantly increased. Increase of cytochrome C in mitochondria and decrease of it in cytosol is significant when compared with unprotected ones which have reversal effects on cytochrome C. The current study presents evidence that sevoflurane-induced cardioprotection at the onset of reperfusion are partly through activation of PKB/Akt and GSK3β.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    CAS  PubMed  Google Scholar 

  2. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588

    CAS  PubMed  Google Scholar 

  3. Deyhimy DI, Fleming NW, Brodkin IG, Liu H (2007) Anesthetic preconditioning combined with postconditioning offers no additional benefit over preconditioning or postconditioning alone. Anesth Analg 105:316–324

    Article  PubMed  Google Scholar 

  4. Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B, Schlack W (2005) The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg 101:1252–1260

    Article  CAS  PubMed  Google Scholar 

  5. Tsutsumi YM, Yokoyama T, Horikawa Y, Roth DM, Patel HH (2007) Reactive oxygen species trigger ischemic and pharmacological postconditioning: in vivo and in vitro characterization. Life Sci 81:1223–1227

    Article  CAS  PubMed  Google Scholar 

  6. Varadarajan SG, An J, Novalija E, Stowe DF (2002) Sevoflurane before or after ischemia improves contractile and metabolic function while reducing myoplasmic Ca2+ loading in intact hearts. Anesthesiology 96:125–133

    Article  CAS  PubMed  Google Scholar 

  7. Feng J, Lucchinetti E, Ahuja P, Pasch T, Perriard JC, Zaugg M (2005) Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta. Anesthesiology 103:987–995

    Article  CAS  PubMed  Google Scholar 

  8. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662

    Article  CAS  PubMed  Google Scholar 

  9. Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC (2005) Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology 102:102–109

    Article  CAS  PubMed  Google Scholar 

  10. Nishino Y, Webb IG, Davidson SM, Ahmed AI, Clark JE, Jacquet S, Shah AM, Miura T, Yellon DM, Avkiran M, Marber MS (2008) Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse. Circ Res 103:307–314

    Article  CAS  PubMed  Google Scholar 

  11. Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G (2009) Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res 104:15–18

    Article  CAS  PubMed  Google Scholar 

  12. Conzen PF, Vollmar B, Habazettl H, Frink EJ, Peter K, Messmer K (1992) Systemic and regional hemodynamics of isoflurane and sevoflurane in rats. Anesth Analg 74:79–88

    Article  CAS  PubMed  Google Scholar 

  13. Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD (2002) Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331–342

    Article  CAS  PubMed  Google Scholar 

  14. Chen HT, Yang CX, Li H, Zhang CJ, Wen XJ, Zhou J, Fan YL, Huang T, Zeng YM (2008) Cardioprotection of sevoflurane postconditioning by activating extracellular signal-regulated kinase 1/2 in isolated rat hearts. Acta Pharmacol Sin 29:931–941

    Article  CAS  PubMed  Google Scholar 

  15. Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M (2008) Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation 117:2761–2768

    Article  CAS  PubMed  Google Scholar 

  16. Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M (2006) PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res 69:178–185

    Article  CAS  PubMed  Google Scholar 

  17. Raphael J, Rivo J, Gozal Y (2005) Isoflurane-induced myocardial preconditioning is dependent on phosphatidylinositol-3-kinase/Akt signalling. Br J Anaesth 95:756–763

    Article  CAS  PubMed  Google Scholar 

  18. Ma K, Cheung SM, Marshall AJ, Duronio V (2008) PI(3, 4, 5)P3 and PI(3, 4)P2 levels correlate with PKB/akt phosphorylation at Thr308 and Ser473, respectively; PI(3, 4)P2 levels determine PKB activity. Cell Signal 20:684–694

    Article  CAS  PubMed  Google Scholar 

  19. Obame FN, Plin-Mercier C, Assaly R, Zini R, Dubois-Randé JL, Berdeaux A, Morin D (2008) Cardioprotective effect of morphine and a blocker of glycogen synthase kinase 3 beta, SB216763 [3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via inhibition of the mitochondrial permeability transition pore. J Pharmacol Exp Ther 326:252–258

    Article  CAS  PubMed  Google Scholar 

  20. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase 3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transtion pore. J Clin Invest 113:1535–1549

    CAS  PubMed  Google Scholar 

  21. Nishihara M, Miura T, Miki T, Tanno M, Yano T, Naitoh K, Ohori K, Hotta H, Terashima Y, Shimamoto K (2007) Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection. J Mol Cell Cardiol 43:564–570

    Article  CAS  PubMed  Google Scholar 

  22. Pagel PS, Krolikowski JG, Neff DA, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC (2006) Inhibition of glycogen synthase kinase enhances isoflurane-induced protection against myocardial infarction during early reperfusion in vivo. Anesth Analg 102:1348–1354

    Article  CAS  PubMed  Google Scholar 

  23. Palma E, Tiepolo T, Angelin A, Sabatelli P, Maraldi NM, Basso E, Forte MA, Bernardi P, Bonaldo P (2009) Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice. Hum Mol Genet 18(11):2024–2031

    Article  CAS  PubMed  Google Scholar 

  24. Crompton M, Costi A, Hayat L (1987) Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. Biochem J 245:915–918

    CAS  PubMed  Google Scholar 

  25. Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787:1395–1401

    Article  CAS  PubMed  Google Scholar 

  26. Tsujimoto Y, Nakagawa T, Shimizu S (2006) Mitochondrial membrane permeability transition and cell death. Biochim Biophys Acta 1757:1297–1300

    Article  CAS  PubMed  Google Scholar 

  27. Cohen MV, Yang XM, Downey JM (2007) The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 115:1895–1903

    Article  PubMed  Google Scholar 

  28. Odagiri K, Katoh H, Kawashima H, Tanaka T, Ohtani H, Saotome M, Urushida T, Satoh H, Hayashi H (2009) Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes. J Mol Cell Cardiol 46(6):989–997

    Article  CAS  PubMed  Google Scholar 

  29. Paillard M, Gomez L, Augeul L, Loufouat J, Lesnefsky EJ, Ovize M (2009) Postconditioning inhibits mPTP opening independent of oxidative phosphorylation and membrane potential. J Mol Cell Cardiol 46:902–909

    Article  CAS  PubMed  Google Scholar 

  30. Saotome M, Katoh H, Yaguchi Y, Tanaka T, Urushida T, Satoh H, Hayashi H (2009) Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 296:H1125–H1132

    Article  CAS  PubMed  Google Scholar 

  31. Correa F, García N, Robles C, Martínez-Abundis E, Zazueta C (2008) Relationship between oxidative stress and mitochondrial function in the post-conditioned heart. J Bioenerg Biomembr 40:599–606

    Article  CAS  PubMed  Google Scholar 

  32. Garciarena CD, Caldiz CI, Correa MV, Schinella GR, Mosca SM, Chiappe de Cingolani GE, Cingolani HE, Ennis IL (2008) Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action. J Appl Physiol 105:1706–1713

    Article  CAS  PubMed  Google Scholar 

  33. Baumgartner HK, Gerasimenko JV, Thorne C, Ferdek P, Pozzan T, Tepikin AV, Petersen OH, Sutton R, Watson AJ, Gerasimenko OV (2009) Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening. J Biol Chem 284:20796–20803

    Article  CAS  PubMed  Google Scholar 

  34. Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC, Pagel PS (2006) Role of Erk1/2, p70s6 K, and eNOS in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anaesth 53:174–182

    Article  PubMed  Google Scholar 

  35. Pravdic D, Sedlic F, Mio Y, Vladic N, Bienengraeber M, Bosnjak ZJ (2009) Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein Kinase C-epsilon-mediated pathway. Anesthesiology 111:267–274

    Article  CAS  PubMed  Google Scholar 

  36. Miura T, Nishihara M, Miki T (2006) Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: role of GSK-3beta in myocardial protection against ischemia/reperfusion injury. J Pharmacol Sci 109(2):162–167

    Article  Google Scholar 

  37. Davidson SM, Hausenloy D, Duchen MR, Yellon DM (2006) Signaling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem Cell Biol 38(3):414–419

    Article  CAS  PubMed  Google Scholar 

  38. Yang J, Zhang XD, Yang J, Ding JW, Liu ZQ, Li SG, Yang R. (2010) The cardioprotective effect of fluvastatin on ischemic injury via down-regulation of toll-like receptor 4. Mol Biol Rep. [Epub ahead of print] PubMed PMID:20127518 (4 2010 Feb)

  39. Yao YT, Li LH, Chen L, Wang WP, Li LB, Gao CQ (2009) Sevoflurane postconditioning protects isolated rat hearts against ischemia-reperfusion injury: the role of radical oxygen species, extracellular signal-related kinases 1/2 and mitochondrial permeability transition pore. Mol Biol Rep. [Epub ahead of print] PubMed PMID:19693689 (2009 Aug 20)

Download references

Acknowledgments

The authors would like to thank Dr. Lv Na-Qiang and Dr. Chang Xin for their technical assistance. This work was supported with the grants from Ph.D. Programs Foundation of Ministry of Education of China (No.20070023012).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Li-Huan Li.

Additional information

Implication statement

The current study presents evidence that activation of PKB/Akt and GSK3β produced by sevoflurane postconditioning in isolated rat hearts takes a crucial role in attenuating ischemia–reperfusion injury.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Scheme of treatment protocols (JPG 14 kb)

Supplementary material 2 (JPG 47 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fang, NX., Yao, YT., Shi, CX. et al. Attenuation of ischemia–reperfusion injury by sevoflurane postconditioning involves protein kinase B and glycogen synthase kinase 3 beta activation in isolated rat hearts. Mol Biol Rep 37, 3763–3769 (2010). https://doi.org/10.1007/s11033-010-0030-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-010-0030-5

Keywords

Navigation