Interplay between SAFE and RISK pathways in sphingosine-1-phosphate-induced cardioprotection.

Purpose: We studied the role of two powerful molecular signalling mechanisms involved in the cardioprotective effect of sphingosine-1-phosphate (S1P), a major component of high density lipoprotein (HDL) against myocardial ischaemic-reperfusion injury, namely the RISK pathway (Akt/Erk), including its downstream target FOXO-1 and, the SAFE pathway (TNF/STAT-3).

Methods: Control hearts from wildtype, TNF deficient (TNF(-/-)) or cardiomyocyte STAT-3 deficient (STAT-3(-/-)) male mice were perfused on a Langendorff apparatus (35 min global ischaemia and 45 min reperfusion). S1P (10 nM) was given at the onset of reperfusion for the first 7 min, with/without STAT-3 or Akt inhibitors, AG490 and wortmannin (W), respectively.