KR-31466, a benzopyranylindol analog, attenuates hypoxic injury through mitochondrial K(ATP) channel and protein kinase C activation in heart-derived H9c2 cells.
In the present study, we investigated whether a novel benzopyranylindol analogue, KR-31466 (KR466) (1-[(2S,3R,4S)-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-6-nitro-2H-1-benzopyran-4-yl]-1H-indole-2-carboxylic acid ethyl ester) can attenuate hypoxic injury in heart-derived H9c2 cells and, if so, whether the protective effect of KR466 is mediated through mitochondrial ATP-sensitive potassium (mtK(ATP)) opening. The treatment of H9c2 cells with KR466 (3 - 30 microM) significantly reduced hypoxia-induced cell death in a concentration-dependent manner, as shown by lactate dehydrogenase release and propidium iodide-uptake. In addition, KR466 (10 microM) significantly reduced the increase in hypoxia-induced TUNEL-positive cells, suggesting its anti-apoptotic potential in H9c2 cells. The protective effects of KR466 were abolished by 5-hydroxydecanoate, a specific blocker of the mtK(ATP) channel, suggesting the involvement of the mtK(ATP) channel in the protective effect of KR466. A specific inhibitor of protein kinase C (PKC), chelerythrine (3 microM), significantly attenuated the protective effect of KR466 against hypoxia-induced cardiac cell death. In conclusion, our results suggest that KR466 can protect H9c2 cells from hypoxia-induced death through mtK(ATP) channel opening and PKC activation.
Jung
Yi-Sook
YS
Department of Physiology, School of Medicine, Ajou University, Suwon, Korea. yisjung@ajou.ac.jp
Jung
Yoon Seok
YS
Kim
Mi-Young
MY
Kim
Min Hwa
MH
Lee
Sunkyung
S
Yi
Kyu Yang
KY
Yoo
Sung Eun
SE
Lee
Soo Hwan
SH
Baik
Eun Joo
EJ
Moon
Chang-Hyun
CH
Cho
Joon Pil
JP
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D007211:Indoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels; D011419:Propidium / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats
D001578:Benzopyrans; D007202:Indicators and Reagents; D007211:Indoles; C482409:KR-31466; D008565:Membrane Proteins; D015221:Potassium Channels; D020011:Protective Agents; C117780:mitochondrial K(ATP) channel; D011419:Propidium; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C