Postconditioning Inhibits Myocardial Apoptosis During Prolonged Reperfusion Via a JAK2-STAT3-Bcl-2 Pathway

Overview

Journal J Biomed Sci

Publisher Biomed Central

Specialty Biology

Date 2011 Aug 4

PMID 21810244

Citations 31

Authors

Yikui Tian

Wenjuan Zhang

Dachuan Xia

Paul Modi

Degang Liang

Minxin Wei

Affiliations

Soon will be listed here.

Abstract

Background: Postconditioning (PostC) inhibits myocardial apoptosis after ischemia-reperfusion (I/R) injury. The JAK2-STAT3 pathway has anti-apoptotic effects and plays an essential role in the late protection of preconditioning. Our aim was to investigate the anti-apoptotic effect of PostC after prolonged reperfusion and the role of the JAK2-STAT3 pathway in the anti-apoptotic effect of PostC.

Methods: Wistar rats were subjected to 30 minutes ischemia and 2 or 24 hours (h) reperfusion, with or without PostC (three cycles of 10 seconds reperfusion and 10 seconds reocclusion at the onset of reperfusion). Separate groups of rats were treated with a JAK2 inhibitor (AG490) or a PI3K inhibitor (wortmannin) 5 minutes before PostC. Immunohistochemistry was used to analyze Bcl-2 protein levels after reperfusion. mRNA levels of Bcl-2 were detected by qRT-PCR. TTC staining was used to detect myocardial infarction size. Myocardial apoptosis was evaluated by TUNEL staining. Western-blot was used to detect p-STAT3 and p-Akt levels after reperfusion.

Results: There was more myocardial apoptosis at 24 h vs 2 h after reperfusion in all groups. PostC significantly reduced myocardial apoptosis and elevated Bcl-2 levels at both 2 and 24 hours after reperfusion. PostC increased p-STAT3 and p-Akt levels after reperfusion. Administration of AG490 reduced p-STAT3 and p-Akt levels and attenuated the anti-apoptotic effect of PostC. Wortmannin also reduced p-Akt levels and attenuated the anti-apoptotic effect of PostC but had no effect on p-STAT3 levels. AG490 abrogated the up-regulation of Bcl-2 by PostC.

Conclusion: PostC may reduce myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. As a downstream target of JAK2 signaling, activation of PI3K/Akt pathway may be necessary in the protection of PostC.

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References

Ruixing Y, Dezhai Y, Hai W, Kai H, Xianghong W, Yuming C . Intramyocardial injection of vascular endothelial growth factor gene improves cardiac performance and inhibits cardiomyocyte apoptosis. Eur J Heart Fail. 2007; 9(4):343-51. DOI: 10.1016/j.ejheart.2006.10.007. View

Zhao Z, Corvera J, Halkos M, Kerendi F, Wang N, Guyton R . Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003; 285(2):H579-88. DOI: 10.1152/ajpheart.01064.2002. View

Jin Y, Lee Y, Kim Y, Seo H, Lee J, Kim H . (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in.... J Pharmacol Exp Ther. 2009; 330(2):440-8. DOI: 10.1124/jpet.108.150342. View

Zhao Z, Nakamura M, Wang N, Velez D, Guyton R, Vinten-Johansen J . Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res. 2000; 94(2):133-44. DOI: 10.1006/jsre.2000.6029. View

Siddiquee K, Zhang S, Guida W, Blaskovich M, Greedy B, Lawrence H . Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A. 2007; 104(18):7391-6. PMC: 1863497. DOI: 10.1073/pnas.0609757104. View

Lacerda L, Somers S, Opie L, Lecour S . Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res. 2009; 84(2):201-8. DOI: 10.1093/cvr/cvp274. View

Hausenloy D, Tsang A, Yellon D . The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med. 2005; 15(2):69-75. DOI: 10.1016/j.tcm.2005.03.001. View

Takahama H, Minamino T, Hirata A, Ogai A, Asanuma H, Fujita M . Granulocyte colony-stimulating factor mediates cardioprotection against ischemia/reperfusion injury via phosphatidylinositol-3-kinase/Akt pathway in canine hearts. Cardiovasc Drugs Ther. 2006; 20(3):159-65. DOI: 10.1007/s10557-006-8285-8. View

Kin H, Wang N, Mykytenko J, Reeves J, Deneve J, Jiang R . Inhibition of myocardial apoptosis by postconditioning is associated with attenuation of oxidative stress-mediated nuclear factor-kappa B translocation and TNF alpha release. Shock. 2008; 29(6):761-8. DOI: 10.1097/SHK.0b013e31815cfd5a. View

10.

Mykytenko J, Kerendi F, Reeves J, Kin H, Zatta A, Jiang R . Long-term inhibition of myocardial infarction by postconditioning during reperfusion. Basic Res Cardiol. 2006; 102(1):90-100. DOI: 10.1007/s00395-006-0625-0. View

11.

Xuan Y, Guo Y, Zhu Y, Wang O, Rokosh G, Messing R . Role of the protein kinase C-epsilon-Raf-1-MEK-1/2-p44/42 MAPK signaling cascade in the activation of signal transducers and activators of transcription 1 and 3 and induction of cyclooxygenase-2 after ischemic preconditioning. Circulation. 2005; 112(13):1971-8. PMC: 3648849. DOI: 10.1161/CIRCULATIONAHA.105.561522. View

12.

Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G . Long-term benefit of postconditioning. Circulation. 2008; 117(8):1037-44. DOI: 10.1161/CIRCULATIONAHA.107.729780. View

13.

Sun H, Wang N, Halkos M, Kerendi F, Kin H, Guyton R . Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis. 2006; 11(9):1583-93. DOI: 10.1007/s10495-006-9037-8. View

14.

Yellon D, Hausenloy D . Myocardial reperfusion injury. N Engl J Med. 2007; 357(11):1121-35. DOI: 10.1056/NEJMra071667. View

15.

Gross E, Hsu A, Gross G . The JAK/STAT pathway is essential for opioid-induced cardioprotection: JAK2 as a mediator of STAT3, Akt, and GSK-3 beta. Am J Physiol Heart Circ Physiol. 2006; 291(2):H827-34. DOI: 10.1152/ajpheart.00003.2006. View

16.

Barry S, Townsend P, Latchman D, Stephanou A . Role of the JAK-STAT pathway in myocardial injury. Trends Mol Med. 2006; 13(2):82-9. DOI: 10.1016/j.molmed.2006.12.002. View

17.

Dawn B, Xuan Y, Guo Y, Rezazadeh A, Stein A, Hunt G . IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2. Cardiovasc Res. 2004; 64(1):61-71. PMC: 3691700. DOI: 10.1016/j.cardiores.2004.05.011. View

18.

Goodman M, Koch S, Fuller-Bicer G, Butler K . Regulating RISK: a role for JAK-STAT signaling in postconditioning?. Am J Physiol Heart Circ Physiol. 2008; 295(4):H1649-56. PMC: 2593522. DOI: 10.1152/ajpheart.00692.2008. View

19.

Shyu W, Lin S, Chiang M, Chen D, Su C, Wang H . Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. J Clin Invest. 2007; 118(1):133-48. PMC: 2129236. DOI: 10.1172/JCI32723. View

20.

Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M . Postconditioning inhibits mitochondrial permeability transition. Circulation. 2005; 111(2):194-7. DOI: 10.1161/01.CIR.0000151290.04952.3B. View