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- Title
Diazoxide acts more as a PKC-ɛ activator, and indirectly activates the mitochondrial K<sub>ATP</sub> channel conferring cardioprotection against hypoxic injury.
- Authors
Kim, M.-Y.; Kim, M. J.; Yoon, I. S.; Ahn, J. H.; Lee, S. H.; Baik, E. J.; Moon, C.-H.; Jung, Y.-S.
- Abstract
Background and purpose:Diazoxide, a well-known opener of the mitochondrial ATP-sensitive potassium (mitoKATP) channel, has been demonstrated to exert cardioprotective effect against ischemic injury through the mitoKATP channel and protein kinase C (PKC). We aimed to clarify the role of PKC isoforms and the relationship between the PKC isoforms and the mitoKATP channel in diazoxide-induced cardioprotection.Experimental approach:In H9c2 cells and neonatal rat cardiomyocytes, PKC-ɛ activation was examined by Western blotting and kinase assay. Flavoprotein fluorescence, mitochondrial Ca2+ and mitochondrial membrane potential were measured by confocal microscopy. Cell death was determined by TUNEL assay.Key results:Diazoxide (100 μM) induced translocation of PKC-ɛ from the cytosolic to the mitochondrial fraction. Specific blockade of PKC-ɛ by either ɛV1-2 or dominant negative mutant PKC-ɛ (PKC-ɛ KR) abolished the anti-apoptotic effect of diazoxide. Diazoxide-induced flavoprotein oxidation was inhibited by either ɛV1-2 or PKC-ɛ KR transfection. Treatment with 5-hydroxydecanoate (5-HD) did not affect translocation and activation of PKC-ɛ induced by diazoxide. Transfection with wild type PKC-ɛ mimicked the flavoprotein-oxidizing effect of diazoxide, and this effect was completely blocked by ɛV1-2 or 5-HD. Diazoxide prevented the increase in mitochondrial Ca2+, mitochondrial depolarization and cytochrome c release induced by hypoxia and all these effects of diazoxide were blocked by ɛV1-2 or 5-HD.Conclusions and Implications:Diazoxide induced isoform-specific translocation of PKC-ɛ as an upstream signaling molecule for the mitoKATP channel, rendering cardiomyocytes resistant to hypoxic injury through inhibition of the mitochondrial death pathway.British Journal of Pharmacology (2006) 149, 1059–1070. doi:10.1038/sj.bjp.0706922; published online 16 October 2006
- Subjects
PROTEIN kinases; HEART cells; ISCHEMIA; CEREBRAL anoxia; CELL death; CONFOCAL microscopy
- Publication
British Journal of Pharmacology, 2006, Vol 149, Issue 8, p1059
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0706922