Identification of caspase-independent PKCepsilon-JNK/p38 MAPK signaling module in response to metabolic inhibition in H9c2 cells.

To understand the molecular mechanism of ischemia-induced cardiac myocyte cell death, H9c2 cells were studied by chemical hypoxia (CH), using metabolic inhibition buffer. CH suppressed the activities of caspase-3, -8, and -9. c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) were activated, whereas extracellular regulated kinase (ERK) was inactivated. Only protein kinase Cepsilon (PKCepsilon) among PKC isotypes was translocated to the membrane fraction implying its activation. Moreover, the administration of PKCepsilon inhibitor suppressed the phosphorylations of JNK/p38 MAPK and reduced CH-induced cell death. An administration of JNK/p38 MAPK inhibitors also decreased CH-induced cell deaths, implying JNK/p38 MAPK's causative roles in the deaths. Collectively, this study identified a novel caspase-independent PKCepsilon-JNK/p38 MAPK signaling module induced by CH in cardiac myocytes. Our data show that the PKCepsilon-JNK/p38 MAPK signaling module contributes to CH-induced H9c2 cell death. This contrasts with previous notions, i.e., PKCepsilon's protective effect against ischemic death. Thus our data suggest that PKCepsilon can mediate alternative signals, i.e., beneficiary or deleterious signals, depending on the cell type, intensity, and/or type of injury.