PMID- 14577849
OWN - NLM
STAT- MEDLINE
DCOM- 20040505
LR  - 20220409
IS  - 0968-0519 (Print)
IS  - 0968-0519 (Linking)
VI  - 9
IP  - 5
DP  - 2003
TI  - Activated protein C signals through the thrombin receptor PAR1 in endothelial 
      cells.
PG  - 317-21
AB  - The anti-inflammatory effects of activated protein C (APC) have lead to its 
      recent approval for the treatment of sepsis. Although the endothelial cell 
      protein C receptor (EPCR) plays a crucial role in APC's protective roles in 
      septicemia, the precise signaling mechanism of the protease APC remains unclear. 
      In fibroblast overexpression systems, we find that APC activates protease 
      activated receptors (PAR) 1 and 2 in an EPCR-dependent manner. Human endothelial 
      cells (HUVECs) express PAR1, PAR2 and EPCR. Stimulation of HUVECs with either 
      APC, or specific receptor activating peptides for PAR1 or PAR2, show that all 
      three agonists induce a very similar set of early response genes as assessed by 
      high density microarray analysis. Only the transcript for monocyte 
      chemo-attractant protein-1 (MCP-1) was selectively induced by APC and the PAR1 
      agonist, but not by the PAR2 agonist. APC-mediated MAP kinase phosphorylation and 
      gene induction were inhibited by cleavage blocking antibodies to PAR1, 
      demonstrating that APC signals exclusively through PAR1 in endothelial cells. 
      MCP-1 is protective in animal models of endotoxemia, suggesting that APC may 
      prevent lethality in sepsis by inducing MCP-1 expression through EPCR-dependent 
      activation of endothelial cell PAR1. These data demonstrate unexpected protective 
      functions of the major thrombin receptor PAR1 in endothelial cells.
FAU - Riewald, Matthias
AU  - Riewald M
AD  - Department of Immunology, The Scripps Research Institute, La Jolla, California 
      92037, USA. riewald@scripps.edu
FAU - Petrovan, Ramona J
AU  - Petrovan RJ
FAU - Donner, Aaron
AU  - Donner A
FAU - Ruf, Wolfram
AU  - Ruf W
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Endotoxin Res
JT  - Journal of endotoxin research
JID - 9433350
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Antibodies, Blocking)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Endothelial Protein C Receptor)
RN  - 0 (Glycoproteins)
RN  - 0 (Procr protein, mouse)
RN  - 0 (Protein C)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (Receptor, PAR-2)
RN  - 0 (Receptors, Cell Surface)
RN  - 74392-49-7 (phenylalanyl-phenylalanyl-arginine chloromethyl ketone)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Animals
MH  - Antibodies, Blocking/pharmacology
MH  - Cell Line
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Endothelial Protein C Receptor
MH  - Endothelium, Vascular/drug effects/*metabolism
MH  - Fibroblasts/drug effects/metabolism
MH  - Glycoproteins/metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Protein C/*metabolism
MH  - Receptor, PAR-1/*metabolism
MH  - Receptor, PAR-2/genetics/metabolism
MH  - Receptors, Cell Surface
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
EDAT- 2003/10/28 05:00
MHDA- 2004/05/07 05:00
CRDT- 2003/10/28 05:00
PHST- 2003/10/28 05:00 [pubmed]
PHST- 2004/05/07 05:00 [medline]
PHST- 2003/10/28 05:00 [entrez]
AID - 10.1179/096805103225002584 [doi]
PST - ppublish
SO  - J Endotoxin Res. 2003;9(5):317-21. doi: 10.1179/096805103225002584.