Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III, 27
Signal transduction pathway of CNP-dependent inhibition of upregulation of PAI-1
expression by TNF-alpha in endothelial cells
Hanna Jerczynska, Czeslaw Cierniewski, Zofia Pawlowska
Department of Molecular & Medical Biophysics, Medical University in Lodz, Poland. Email:
pawlow@zdn.am.lodz.pl
Plasminogen activator inhibitor type 1 (PAI-1) plays a fundamental role in regulation of the
fibrinolytic system. PAI-1 synthesis is upregulated by multiple factors, but only few are
known to be able to decrease PAI-1 expression. In our previous study we found that C-type
natriuretic peptide (CNP), which modulates salt and water balance as well as vascular tone,
was an effective inhibitor of PAI-1 synthesis and release from endothelial cells, it also reveals
stronger inhibitory activity for TNF-alpha - stimulated cells. The signaling pathways required
for this effect have not been elucidated. It was reported that NF-kB is involved in TNFregulated
PAI-1 production. We have evidenced that the activation of MAPK kinase cascade
is a necessary step in induction of PAI-1 expression by TNF in endothelial cells. In this study,
the effects of signal transduction inhibitors on TNF-induced PAI-1 expression in the presence
of CNP were examined. We used PD 98059, an ERK1/2 inhibitor, LY 294002, a PI3K/Akt
inhibitor, and 8-bromo-cGMP, a soluble analog of cGMP to characterize the signal
transduction pathway involved in CNP action in human endothelial cells. Involvement of NFkB
activation in this process was also investigated.
Our results imply that CNP inhibition of TNF-activated PAI-1 gene expression takes place via
regulation of signal transduction pathways involving PI3K/Akt and cGMP-dependent protein
kinase, possibly by inhibiting NF-kB-dependent pathways. The activation of ERK seems not
to be implicated in this process. Thus, our results explain at least in part the mechanism
involved in PAI-1 expression inhibition by CNP in TNF-stimulated endothelial cells.
Supported by grants: QLK3-CT-2002-30326 (5th EU FP) and Medical University of Lodz,
Poland.
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