Role of the Mitochondrial Permeability Transition Pore in TNF-α-Induced Recovery of Ventricular Contraction and Reduction of Infarct Size in Isolated Rat Hearts Subjected to Ischemia/Reperfusion

Abstract

Pretreatment with tumor necrosis factor-α (TNF-α) is known to trigger cardioprotection. TNF-α can activate multiple downstream signaling cascades. However, it is not known whether the mitochondrial permeability transition pore (MitoPTP) is involved in TNF-α -induced cardioprotection. In the present study, we examined whether TNF-α inhibits MitoPTP opening. In isolated rat hearts subjected to 30 min regional ischemia and 120 min reperfusion, pretreatment with 10 U/ml TNF-α for 7 min followed by 10 min washout improved the recovery of left ventricular developed pressure (LVDP) and rate-pressure product (RPP = LVDP × heart rate) during reperfusion and reduced the infarct size. Administration of 20 μ mol/L atractyloside, a MitoPTP opener, for 20 min (last 5 min of ischemia and first 15 min of reperfusion) and pretreatment with 1 μ inhibitor of the Ca2+-activated K+mol/L paxilline, an channel, for 5 min before ischemia, attenuated the recovery of LVDP and RPP and the reduction of infarct size induced by TNF-α. The findings indicate that, in the isolated heart model, TNF-α protects myocardium against ischemia/reperfusion injury via inhibiting MitoPTP opening as well as by activating the Ca2+-activated K+channel.