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KR-31378, a novel benzopyran analog, attenuates hypoxia-induced cell death via mitochondrial KATP channel and protein kinase C-epsilon in heart-derived H9c2 cells.

Authors
Moon, CH; Kim, MY; Kim, MJ; Kim, MH; Lee, S; Yi, KY; Yoo, SE; Lee, DH; Lim, H; Kim, HS; Lee, SH; Baik, EJ; Jung, YS
Citation
European journal of pharmacology, 506(1):27-35, 2004
Journal Title
European journal of pharmacology
ISSN
0014-29991879-0712
Abstract
A novel compound KR-31378 [(2S,3S,4R)-N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methly-2-dimethoxy-methly-2H-benzo-pyran-4-yl)-N-benzylguanidine] has been demonstrated as an anti-ischemic agent in rat heart and brain. Here, we report the effects of this compound on hypoxia-induced cell death and possible signaling pathways in heart-derived H9c2 cells. Treatment with KR-31378 (3-30 microM) 1 h before and during hypoxia significantly reduced hypoxia-induced cell death in a concentration-dependent manner. In addition, increase in hypoxia-induced transferase UTP nick end labeling (TUNEL)-positive cells was reduced by KR-31378, suggesting its antiapoptotic potential in H9c2 cells. The protective effect conferred by KR-31378 (10 microM) was abolished by cotreatment with 5-hydroxydecanoate (5HD), a specific blocker of the mitochondrial KATP (mtKATP) channel, but not by HMR-1883 (1-[[5-[2-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-methylthiourea), a specific blocker of the sarcolemmal KATP channel. We observed that the treatment with KR-31378 could increase the expression of protein kinase C (PKC)-epsilon protein, but not other PKC isotypes (-alpha, -beta, -delta, -zeta), in the particulate fraction. This increased level of PKC-epsilon was sustained during the hypoxic period up to 8 h. In addition, our results showed that treatment with KR-31378 induced the expression of PKC-epsilon mRNA as early as 15 min after the treatment. A specific inhibitor for PKC-epsilon isoform, epsilonV1-2, completely blocked the protective effect of KR-31378 against hypoxia-induced cell death. In conclusion, our results suggest that KR-31378 can protect cultured H9c2 cells from hypoxia-induced death via the mtKATP channel and PKC-epsilon.
MeSH terms
AnimalsApoptosis/*drug effectsBlotting, WesternCell HypoxiaCell LineDecanoic Acids/pharmacologyDose-Response Relationship, DrugGuanidines/*pharmacologyHydroxy Acids/pharmacologyIn Situ Nick-End LabelingMembrane Proteins/antagonists & inhibitors/*metabolismMitochondria, Heart/metabolismMyocytes, Cardiac/cytology/*drug effects/metabolismPotassium Channels/metabolismProtein Kinase C/*metabolismProtein Kinase C-epsilonPyrans/*pharmacologySulfonamides/pharmacologyThiourea/*analogs & derivatives/pharmacologyTime Factors
DOI
10.1016/j.ejphar.2004.10.037
PMID
15588621
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
문, 창현이, 수환백, 은주정, 이숙
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