PKCepsilon modulates NF-kappaB 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)-kappaB, and mitogen-activated protein kinases (MAPKs) are essential signaling elements in ischemic preconditioning. In the present study, we examined whether activation of PKCepsilon affects the activation of NF-kappaB in cardiac myocytes and whether MAPKs are mediators of this signaling event. Activation of PKCepsilon (+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-kappaB (+164%) and activator protein (AP)-1 (+127%) but not that of Elk-1. Activation of PKCeta did not have an effect on these transcription factors. Activation of PKCepsilon also enhanced the phosphorylation activities of the p44/p42 MAPKs and the p54/p46 c-Jun NH(2)-terminal kinases (JNKs). PKCepsilon-induced activation of NF-kappaB 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-kappaB and AP-1 as downstream targets of PKCepsilon, thereby establishing a molecular link between activation of PKCepsilon and activation of NF-kappaB 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.
Li
R C
RC
Experimental Research Laboratory, Division of Cardiology, University of Louisville and the Jewish Hospital Heart and Lung Research Institute, Louisville, Kentucky 40202, USA.
Ping
P
P
Zhang
J
J
Wead
W B
WB
Cao
X
X
Gao
J
J
Zheng
Y
Y
Huang
S
S
Han
J
J
Bolli
R
R
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011817:Rabbits; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D007527:Isoenzymes; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D004247:DNA; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases