The mitochondrial permeability transition pore and the Ca2+-activated K+ channel contribute to the cardioprotection conferred by tumor necrosis factor-α

Pretreatment with tumor necrosis factor-alpha (TNF-alpha) 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 Ca2+-activated K+ channel (K-Ca channel) are involved in the TNF-alpha-induced cardioprotection. In the present Study, we examined whether TNF-alpha. inhibits pore opening and activates the K-Ca channel in the cardiciprotection. In isolated rat hearts Subjected to 30 min of regional ischemia and 120 min of reperfusion, pretreatment with 10 U/mil TNF-alpha for 7 min followed by 10 min washout improved the recovery of rate-pressure product (RPP = left ventricular developed pressure X heart rate) and coronary flow (CF) during reperfusion. and reduced the infarct size and release of lactate dehydrogenase (LDH). Administration of 20 mu mol/L atractyloside, a pore opener, for the last 5 min of ischemia and first 15 min of reperfusion, and pretreatment with 1 mu mol/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-alpha. On the other hand, administration of 10 mu mol/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 mu mol/L cyclosporin A for the last 5 min of ischemia and first 15 min of reperfusion showed similar effects to those of TNF-alpha and they were not attenuated by paxilline. In mitochondria isolated from hearts pretreated with 10 U/ml TNF-alpha for 7 min, a significant inhibition of Ca2+-induced was observed. Furthermore, paxilline attenuated the inhibition of Ca2+-induced mitochondrial swelling by TNF-alpha. These findings indicate that TNF-alpha 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. (c) 2005 Elsevier Ltd. All rights reserved.