124 278

Cited 0 times in

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

Authors
Kim, MY; Kim, MJ; Yoon, IS; Ahn, JH; Lee, SH; Baik, EJ; Moon, CH; Jung, YS
Citation
British journal of pharmacology, 149(8):1059-1070, 2006
Journal Title
British journal of pharmacology
ISSN
0007-11881476-5381
Abstract
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
DOI
10.1038/sj.bjp.0706922
PMID
17043673
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
이, 수환백, 은주문, 창현정, 이숙
Full Text Link
Files in This Item:
1059-1070.pdfDownload
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse