Activated protein C downregulates p38 mitogen-activated protein kinase and improves clinical parameters in an in-vivo model of septic shock.
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 plasma TNF-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.
Nold
Marcel F
MF
Department of Pediatrics, J.W. Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. mfnold@hotmail.com
Nold-Petry
Claudia A
CA
Fischer
Doris
D
Richter
Bernd
B
Blaheta
Roman
R
Pfeilschifter
Josef
J
Muhl
Heiko
H
Schranz
Dietmar
D
Veldman
Alex
A
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008099:Liver / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy*; D013552:Swine; D016159:Tumor Suppressor Protein p53; D014471:Umbilical Veins / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000187:drug effects* / Q000378:metabolism
D011486:Protein C; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases