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modulates NF-
B and
AP-1 via mitogen-activated protein kinases in adult
rabbit cardiomyocytes
1 Experimental Research Laboratory, Division of Cardiology, 2 Department of Physiology and Biophysics, University of Louisville and the Jewish Hospital Heart and Lung Research Institute, Louisville, Kentucky 40202; and 3 Division of Immunology, Scripps Institute of Molecular Medicine, La Jolla, California 92037
We have previously shown that
protein kinase C (PKC)-
, nuclear factor (NF)-
B, and
mitogen-activated protein kinases (MAPKs) are essential signaling
elements in ischemic preconditioning. In the present study, we examined
whether activation of PKC
affects the activation of NF-
B in
cardiac myocytes and whether MAPKs are mediators of this signaling
event. Activation of PKC
(+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-
B (+164%) and activator protein (AP)-1 (+127%) but not that of
Elk-1. Activation of PKC
did not have an effect on these
transcription factors. Activation of PKC
also enhanced the
phosphorylation activities of the p44/p42 MAPKs and the p54/p46 c-Jun
NH2-terminal kinases (JNKs). PKC
-induced activation of
NF-
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-
B and AP-1 as downstream targets of PKC
, thereby
establishing a molecular link between activation of PKC
and
activation of NF-
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.
protein kinase C
; activator protein-1; nuclear
factor-
B
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