PKCε modulates NF-κB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes

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Abstract
We have previously shown that protein kinase C (PKC)-ε, nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPKs) are essential signaling elements in ischemic preconditioning. In the present study, we examined whether activation of PKCε affects the activation of NF-κB in cardiac myocytes and whether MAPKs are mediators of this signaling event. Activation of PKCε (+108% above control) in adult rabbit cardiomyocytes to a degree that has been previously shown to protect myocytes against hypoxic injury increased the DNA-binding activity of NF-κB (+164%) and activator protein (AP)-1 (+127%) but not that of Elk-1. Activation of PKCη did not have an effect on these transcription factors. Activation of PKCε also enhanced the phosphorylation activities of the p44/p42 MAPKs and the p54/p46 c-Jun NH2-terminal kinases (JNKs). PKCε-induced activation of NF-κB and AP-1 was completely abolished by inhibition of the p44/p42 MAPK pathway with PD98059 and by inhibition of the p54/p46 JNK pathway with a dominant negative mutant of MAPK kinase-4, indicating that both signaling pathways are necessary. Taken together, these data identify NF-κB and AP-1 as downstream targets of PKCε, thereby establishing a molecular link between activation of PKCε and activation of NF-κB and AP-1 in cardiomyocytes. The results further demonstrate that both the p44/p42 MAPK and the p54/p46 JNK signaling pathways are essential mediators of this event.

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