Preconditioning-like cardioprotective effect of the platelet-activating factor: pre- and post-ischemic signaling pathway

We previously showed that endogenous platelet activating factor (PAF) is involved in heart preconditioning. We studied the intracellular pathways involved in PAF-induced cardioprotection. In Group 1 control hearts, Langendorff-perfused rat hearts underwent 30 minutes ischemia and 2 hours of reperfusion. Group 2 hearts, before ischemia, were perfused for 19 min with PAF (2x10–11 M); Groups 3 and 4 hearts were co-infused with PAF and N-acetyl-L-cysteine or 5-hydroxydecanoate to scavenge ROS or to block mitochondrial-ATP-sensitive K+ (mKATP) channels, respectively. In Group 5, PAF pretreated hearts were infused during the initial 20 min of reperfusion with Atractyloside, a mitochondrial permeability transition pore (mPTP) opener. Left ventricular pressure and infarct size were determined. In sixteen additional hearts the phosphorylation of kinases by PAF was determined both in pre- and post-ischemic period. PAF-pretreatment reduced infarct size (33±4% vs 64±4.6 % of the area at risk of control hearts) and improved pressure recovery. Infarct-sparing effect of PAF was abolished by N-acetyl-L-cysteine, 5-hydroxydecanoate and Atractyloside. PAF-pretreatment enhanced the phosphorylation/activation of protein kinases (PKCε and PKB/Akt) both in the pre- and post-ischemic period, and preserved the phosphorylation/inactivation of glycogen synthase kinase-3β (GSK-3β) in reperfusion. Thus, PAF-pretreatment involves activation of mKATP channels and redox signaling in pre-ischemic phase, and PKB/Akt activation, GSK-3β inhibition and closing of mPTP in reperfusion, which explain cardioprotection.