Abstract
The coagulant and inflammatory exacerbation in sepsis is counterbalanced by the protective protein C (PC) pathway. Activated PC (APC) was shown to use the endothelial cell PC receptor (EPCR) as a coreceptor for cleavage of protease activated receptor 1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all APC-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP-1), which was selectively induced by activation of PAR1, but not PAR2. Thus, the prototypical thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blood Coagulation Factors*
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Cell Line
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Cells, Cultured
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Chemokine CCL2 / genetics
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DNA-Binding Proteins / genetics
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism*
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Enzyme Activation
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Gene Expression Profiling
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Gene Expression Regulation
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Humans
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Oligonucleotide Array Sequence Analysis
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Phosphorylation
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Protein C / metabolism*
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Receptor, PAR-1
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Receptor, PAR-2
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Receptors, Cell Surface / metabolism
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Receptors, Thrombin / agonists
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Receptors, Thrombin / metabolism*
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Signal Transduction
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Thrombin / metabolism
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Transcription Factors / genetics
Substances
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Blood Coagulation Factors
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Chemokine CCL2
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DNA-Binding Proteins
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NR4A1 protein, human
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Nr4a1 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Protein C
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Receptor, PAR-1
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Receptor, PAR-2
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Receptors, Cell Surface
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Receptors, Thrombin
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Transcription Factors
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activated protein C receptor
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Mitogen-Activated Protein Kinases
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Thrombin