The mitochondrial permeability transition pore and the Ca 2+-activated K + channel contribute to the cardioprotection conferred by tumor necrosis factor-α

Abstract

Pretreatment with tumor necrosis factor-α (TNF-α) is known to trigger cardioprotection and it can activate multiple downstream signaling cascades. However, it is not known whether the mitochondrial permeability transition pore and the Ca 2+-activated K + channel (K Ca channel) are involved in the TNF-α-induced cardioprotection. In the present study, we examined whether TNF-α inhibits pore opening and activates the K Ca channel in the cardioprotection. In isolated rat hearts subjected to 30 min of regional ischemia and 120 min of reperfusion, pretreatment with 10 U/ml TNF-α for 7 min followed by 10 min washout improved the recovery of rate-pressure product (RPP = left ventricular developed pressure × heart rate) and coronary flow (CF) during reperfusion, and reduced the infarct size and release of lactate dehydrogenase (LDH). Administration of 20 μmol/L atractyloside, a pore opener, for the last 5 min of ischemia and first 15 min of reperfusion, and pretreatment with 1 μmol/L paxilline, an inhibitor of the K Ca channel, for 5 min before ischemia, attenuated the recovery of RPP and CF, and the reductions of infarct size and release of LDH induced by TNF-α. On the other hand, administration of 10 μmol/L NS 1619, an opener of the K Ca channel, for 10 min before ischemia, decreased the infarct size and LDH release, and improved contractile functions and CF; these effects were attenuated by atractyloside. Pretreatment with 0.2 μmol/L cyclosporin A for the last 5 min of ischemia and first 15 min of reperfusion showed similar effects to those of TNF-α, and they were not attenuated by paxilline. In mitochondria isolated from hearts pretreated with 10 U/ml TNF-α for 7 min, a significant inhibition of Ca 2+-induced swelling was observed. Furthermore, paxilline attenuated the inhibition of Ca 2+-induced mitochondrial swelling by TNF-α. These findings indicate that TNF-α protects the myocardium against ischemia and reperfusion injury by inhibiting mitochondrial permeability transition pore opening as well as activating K Ca channels, probably the mitochondrial K Ca channel, which is upstream from the pore.