Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway?

Lethal reperfusion injury is now recognized as a major limitation of current reperfusion therapy by primary percutaneous coronary intervention for acute myocardial infarction. Interestingly, the heart itself is capable of activating an intrinsic protective signaling programme to limit cell death during reperfusion. Tumor necrosis factor alpha (TNFalpha) is a cytokine generally thought to contribute to myocardial dysfunction in ischemia/reperfusion or heart failure. We review evidence that TNFalpha can paradoxically initiate the activation of a novel protective pathway against reperfusion injuries that we have named the Survivor Activating Factor Enhancement (SAFE) pathway. This path requires the activation of the signal transducer and activator of transcription 3 (STAT-3) and it can successfully lessen cardiomyocyte death at the time of reperfusion, independently of the activation of the already well-described Reperfusion Injury Salvage Kinase (RISK) pathway (which includes activation of Akt and Erk 1/2). Emerging knowledge on this novel protective path is presented here with the aim of unravelling its interaction with the RISK pathway and its potential human application to protect against lethal reperfusion injury.