KR-31378 protects cardiac H9c2 cells from chemical hypoxia-induced cell death via inhibition of JNK/p38 MAPK activation.
Using a metabolic inhibition buffer as an ischemic model, we show here that KR-31378, a cardioselective ATP-sensitive potassium channel opener, protects H9c2 cells from chemical hypoxia (CH)-induced cell death. Our previous study showed that CH downregulated caspase activities, but led to differential activation of mitogen-activated protein kinases (MAPKs) in H9c2 cells. The repression of CH-induced c-jun N-terminal kinase (JNK)/p38 MAPK activation resulted in partial protection against CH- induced cell death, implying JNK/p38 MAPK's causative role in CH-induced cell death. This study furthers that research and examines if KR-31378's protective effect came from modulating MAPK activity and/or caspase activity in H9c2 cells. Although KR-31378 did not restore downregulated caspase-3 activity, it did block the activation of JNK and p38 MAPK in a dose-dependent manner. Extracellular signal-regulated kinase activity was not recovered by KR-31378 treatment. CH-induced reactive oxygen species (ROS) generation was suppressed by KR-31378. Thus our results indicate that the cardioprotective effect of KR-31378 in CH is due, at least in part, to the differential inhibition of MAPKs.
Jung
Yong-Sam
YS
Research Center for Biomedicinal Resources, Department of Genetic Engineering, PaiChai University, Daejeon 302-735, Korea.
Lee
Dong-Ha
DH
Lim
Hong
H
Yi
Kyu Yang
KY
Yoo
Sung-Eun
SE
Kim
Eunhee
E
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009206:Myocardium / Q000166:cytology*; D009570:Nitriles / Q000494:pharmacology; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000873:Anthracenes; D002070:Butadienes; D006146:Guanidines; D007093:Imidazoles; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D009570:Nitriles; D011714:Pyrans; D011725:Pyridines; D017382:Reactive Oxygen Species; C113580:U 0126; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580