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Diazoxide acts more as a PKC-epsilon activator, and indirectly activates the mitochondrial K(ATP) channel conferring cardioprotection against hypoxic injury.

Kim, MY; Kim, MJ; Yoon, IS; Ahn, JH; Lee, SH; Baik, EJ; Moon, CH; Jung, YS
British journal of pharmacology, 149(8):1059-1070, 2006
Journal Title
British journal of pharmacology
BACKGROUND AND PURPOSE: Diazoxide, a well-known opener of the mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, has been demonstrated to exert cardioprotective effect against ischemic injury through the mitoK(ATP) channel and protein kinase C (PKC). We aimed to clarify the role of PKC isoforms and the relationship between the PKC isoforms and the mitoK(ATP) channel in diazoxide-induced cardioprotection.

EXPERIMENTAL APPROACH: In H9c2 cells and neonatal rat cardiomyocytes, PKC-epsilon activation was examined by Western blotting and kinase assay. Flavoprotein fluorescence, mitochondrial Ca(2+) and mitochondrial membrane potential were measured by confocal microscopy. Cell death was determined by TUNEL assay.

KEY RESULTS: Diazoxide (100 microM) induced translocation of PKC-epsilon from the cytosolic to the mitochondrial fraction. Specific blockade of PKC-epsilon by either epsilonV1-2 or dominant negative mutant PKC-epsilon (PKC-epsilon KR) abolished the anti-apoptotic effect of diazoxide. Diazoxide-induced flavoprotein oxidation was inhibited by either epsilonV1-2 or PKC-epsilon KR transfection. Treatment with 5-hydroxydecanoate (5-HD) did not affect translocation and activation of PKC-epsilon induced by diazoxide. Transfection with wild type PKC-epsilon mimicked the flavoprotein-oxidizing effect of diazoxide, and this effect was completely blocked by epsilonV1-2 or 5-HD. Diazoxide prevented the increase in mitochondrial Ca(2+), mitochondrial depolarization and cytochrome c release induced by hypoxia and all these effects of diazoxide were blocked by epsilonV1-2 or 5-HD.

CONCLUSIONS AND IMPLICATIONS: Diazoxide induced isoform-specific translocation of PKC-epsilon as an upstream signaling molecule for the mitoK(ATP) channel, rendering cardiomyocytes resistant to hypoxic injury through inhibition of the mitochondrial death pathway.
MeSH terms
AnimalsAnoxia/pathology*Anoxia/prevention & control*Antihypertensive Agents/pharmacology*Blotting, WesternCalcium/metabolismCardiotonic Agents*Cell LineCytosol/metabolismDiazoxide/pharmacology*Enzyme Activators/pharmacology*Flavoproteins/metabolismIn Situ Nick-End LabelingMembrane Potentials/drug effectsMitochondria, Heart/drug effectsMitochondria, Heart/metabolismMyocytes, Cardiac/drug effectsMyocytes, Cardiac/metabolismPlasmids/geneticsPotassium Channels, Inwardly Rectifying/agonists*Potassium Channels, Inwardly Rectifying/metabolism*Protein Kinase C-epsilon/geneticsProtein Kinase C-epsilon/metabolism*RatsRats, Sprague-DawleyTransfection
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Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
이, 수환백, 은주문, 창현정, 이숙
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