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Am J Physiol Heart Circ Physiol 279: H1679-H1689, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 4, H1679-H1689, October 2000

PKCepsilon modulates NF-kappa B and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes

Richard C. X. Li1, Peipei Ping1,2, Jun Zhang2, William B. Wead2, Xinan Cao2, Jiuming Gao2, Yuting Zheng2, Shuang Huang3, Jiahuai Han3, and Roberto Bolli1,2

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)-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 PKCepsilon affects the activation of NF-kappa B 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-kappa B (+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 NH2-terminal kinases (JNKs). PKCepsilon -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 PKCepsilon , thereby establishing a molecular link between activation of PKCepsilon 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.

protein kinase Cepsilon ; activator protein-1; nuclear factor-kappa B


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