Activated protein C downregulates p38 mitogen-activated protein kinase and improves clinical parameters in an in-vivo model of septic shock

Marcel F. Nold; Claudia A. Nold-Petry; Doris Fischer; Bernd Richter; Roman Blaheta; Josef Pfeilschifter; Heiko Muhl; Dietmar Schranz; Alex Veldman

doi:10.1160/TH07-01-0052

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(05): 1118-1126
DOI: 10.1160/TH07-01-0052

Animal Models

Schattauer GmbH

Activated protein C downregulates p38 mitogen-activated protein kinase and improves clinical parameters in an in-vivo model of septic shock

Authors

Marcel F. Nold

¹Departments of Pediatrics, J.W. Goethe-University Hospital, Frankfurt
Claudia A. Nold-Petry

⁴Pharmazentrum Frankfurt / ZAFES, J.W. Goethe-University Hospital, Frankfurt;

⁵Pediatric Heart Center, J. Liebig-University Hospital, Giessen, Germany
Doris Fischer

¹Departments of Pediatrics, J.W. Goethe-University Hospital, Frankfurt
Bernd Richter

²Pediatric Surgery, J.W. Goethe-University Hospital, Frankfurt
Roman Blaheta

³Urology, J.W. Goethe-University Hospital, Frankfurt
Josef Pfeilschifter

⁴Pharmazentrum Frankfurt / ZAFES, J.W. Goethe-University Hospital, Frankfurt;
Heiko Muhl

⁴Pharmazentrum Frankfurt / ZAFES, J.W. Goethe-University Hospital, Frankfurt;
Dietmar Schranz

⁵Pediatric Heart Center, J. Liebig-University Hospital, Giessen, Germany
Alex Veldman

⁵Pediatric Heart Center, J. Liebig-University Hospital, Giessen, Germany

Abstract

Summary

Despite the success of the anti-coagulant protease protein C (PC) in treating septic shock in humans, the signaling pathways used are still unclear. To explore the effects of treatment with PC zymogen and its activated form aPC in a setting of sepsis, we employed a piglet model of endotoxic shock. In the aPC group, we observed a 65%-90% reduction in plasmaTNF-alpha levels and a concomitant clinical improvement. Unexpectedly, administration of aPC also resulted in stabilization of the plasma pH above 7.2. Moreover, phosphorylated p38 mitogen-activated protein kinase (p38MAPK) was virtually absent in the livers of those piglets receiving aPC. In cultured human umbilical vein endothelial cells, we observed that nanomolar concentrations of PC and aPC inhibited the phosphorylation of p38MAPK. Furthermore, we showed that the regulation of the pro-apoptotic cell cycle regulator p53 by PC and aPC is dependent on the reduction of p38MAPK activation. The transduction of these effects involves all three receptors associated with protein C signaling, namely endothelial protein C receptor, protease-activated receptor 1, and sphingosine 1-phosphate receptor 1. Ultimately, this study elucidates novel signaling pathways regulated by protein C and emphasises the pivotal importance of its multiple modes of action beyond anticoagulation. APC’s clinical success may, in part, be due to p38MAPK inhibition.

Keywords

Protein C - sepsis - signal transduction - p38MAPK - apoptosis

Full Text

References

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