Cardiovascular Research Advance Access originally published online on August 7, 2009
Cardiovascular Research 2009 84(2):201-208; doi:10.1093/cvr/cvp274
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway
Hatter Cardiovascular Research Institute, Cardioprotection Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, Cape Town, South Africa
* Corresponding author. Tel: +27 21 406 6358; fax: +27 21 447 8789. E-mail address: lydia.lacerda{at}uct.ac.za
Aims: Ischaemic postconditioning (IPostC) is a powerful protective phenomenon that activates prosurvival intrinsic signalling cascades to limit reperfusion injury. We propose that IPostC confers its infarct-sparing effect via activation of the newly described prosurvival Survivor Activating Factor Enhancement (SAFE) pathway, which involves the activation of the cytokine tumour necrosis factor alpha (TNF
) and signal transducer and activator of transcription-3 (STAT-3).
Methods and results: Isolated ischaemic/reperfused hearts from TNF knockout, TNF receptor-1 knockout, TNF receptor-2 knockout, cardiomyocyte-specific STAT-3-deficient mice or their respective wild-type, (TNF-WT) or (STAT-3-WT), were postconditioned by ischaemic episodes (IPostC) or with exogenous TNF (0.5 µg/L) (TNF-PostC) at the onset of reperfusion. IPostC reduced infarct size (IS) in TNF-WT and TNFR1–/– hearts (by 33 and 27%, respectively, P < 0.05), whereas hearts from TNF–/– or TNFR2–/– failed to be postconditioned. TNF-PostC reduced IS by 37% (P < 0.05) in STAT-3-WT hearts but failed to protect cardiac-specific STAT-3–/– hearts. Administration of wortmannin, an inhibitor of PI-3 kinase/Akt, or PD98059, an inhibitor of extracellular regulated kinase 1/2 (Erk1/2), during the postconditioning stimulus did not abolish the infarct-sparing effect of TNF-PostC. AG490, an inhibitor of STAT-3, abrogated the protective effect of TNF. Western blot analysis did not demonstrate the involvement of Akt or Erk1/2 in TNF-PostC, whereas STAT-3 phosphorylation was increased in both IPostC and TNF-PostC.
Conclusion: The protective effect of the SAFE pathway is shown in IPostC, with the activation of TNF, its receptor type 2, and STAT-3. This signalling cascade is activated independently of the well-known Reperfusion Injury Salvage Kinases (RISK) pathway, which involves the kinases Akt and Erk1/2.
KEYWORDS Infarction; Ischaemia; Preconditioning; Postconditioning; Reperfusion
Time for primary review: 21 days
Related Article
CiteULike 
Connotea 
Del.icio.us What's this?
Cardiovasc Res 2009 84: 173-175.
This article has been cited by other articles:
|
|
 |
|
  G. Heusch No RISK, no ... cardioprotection? A critical perspective Cardiovasc Res, November 1, 2009; 84(2): 173 - 175. [Full Text] [PDF]
|
|