Opening of mitochondrial K_ATP channel occurs downstream of PKC-ε activation in the mechanism of preconditioning

Abstract

We examined whether the mitochondrial ATP-sensitive K channel (K(ATP)) is an effector downstream of protein kinase C-epsilon (PKC-epsilon) in the mechanism of preconditioning (PC) in isolated rabbit hearts. PC with two cycles of 5-min ischemia/5-min reperfusion before 30-min global ischemia reduced infarction from 50.3 +/- 6.8% of the left ventricle to 20.3 +/- 3.7%. PC significantly increased PKC-epsilon protein in the particulate fraction from 51 +/- 4% of the total to 60 +/- 4%, whereas no translocation was observed for PKC-delta and PKC-alpha. In mitochondria separated from the other particulate fractions, PC increased the PKC-epsilon level by 50%. Infusion of 5-hydroxydecanoate (5-HD), a mitochondrial K(ATP) blocker, after PC abolished the cardioprotection of PC, whereas PKC-epsilon translocation by PC was not interfered with 5-HD. Diazoxide, a mitochondrial K(ATP) opener, infused 10 min before ischemia limited infarct size to 5.2 +/- 1.4%, but this agent neither translocated PKC-epsilon by itself nor accelerated PKC-epsilon translocation after ischemia. Together with the results of earlier studies showing mitochondrial K(ATP) opening by PKC, the present results suggest that mitochondrial K(ATP)-mediated cardioprotection occurs subsequent to PKC-epsilon activation by PC.

Endogenous Calcitonin Gene-related Peptide Protects Human Alveolar Epithelial Cells through Protein Kinase Cϵ and Heat Shock Protein

“…Upon activation, PKC⑀ translocates to a unique subcellular locale next to its specific substrates, including the mitochondrial K ϩ ATP channel (24). Indeed, we have detected the CGRP-induced membrane translocation of PKC⑀ in A549 cells.…”

Cardioprotective effect of preconditioning is more efficient than postconditioning in rats submitted to cardiac ischemia and reperfusion

“…The opening these channels involves the epsilon isoform of protein kinase C (PKCε) 18 , preventing hyperpolarization of electrical potential of mitochondrial membrane 19 avoiding accumulation of mitochondrial Ca 2+ , prolonged opening of MPTP, release of cytochrome c and apoptosis 20,21 .…”

Early opening of sarcolemmal ATP-sensitive potassium channels is not a key step in PKC-mediated cardioprotection

“…Recently, protein kinases forming part of the RISK pathway, specifically PKCε, have been implicated in the IPC phenomenon [13]. Experimentally, in cardioprotective protocols, PKCε is translocated to the mitochondria [13][14][15]. It has been demonstrated in differing tissue types that K ATP channels can be regulated by a number of different cell signaling pathways; in particular by PKA and PKC [16].…”