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

We have previously shown that protein kinase C (PKC)-epsilon, nuclear factor (NF)-kappa B, and mitogen-activated protein kinases (MAPKs) are essential signaling elements in ischemic preconditioning. In the present study, we examined whether activation of PKC epsilon affects the activation of NF-kappa B in cardiac myocytes and whether MAPKs are mediators of this signaling event. Activation of PKC epsilon (+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-kappa B (+164%) and activator protein (AP)-1 (+127%) but not that of Elk-1. Activation of PKC eta did not have an effect on these transcription factors. Activation of PKC epsilon also enhanced the phosphorylation activities of the p44/p42 MAPKs and the p54/p46 c-Jun NH2-terminal kinases (JNKs). PKC epsilon-induced activation of NF-kappa B 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-kappa B and AP-1 as downstream targets of PKC epsilon, thereby establishing a molecular link between activation of PKC epsilon and activation of NF-kappa B 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.