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.
Eur J Pharmacol
; 506(1): 27-35, 2004 Dec 03.
Article
em En
| MEDLINE
| ID: mdl-15588621
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piranos
/
Tioureia
/
Proteína Quinase C
/
Apoptose
/
Miócitos Cardíacos
/
Guanidinas
/
Proteínas de Membrana
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Coréia do Sul