TY - JOUR
T1 - Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells
AU - Camerer, Eric
AU - Kataoka, Hiroshi
AU - Kahn, Mark
AU - Lease, Katy
AU - Coughlin, Shaun R.
PY - 2002/5/3
Y1 - 2002/5/3
N2 - The coagulation protease Factor Xa (Xa)1 triggers a variety of cellular responses that may be important for inflammatory reactions to tissue injury. Protease-activated receptors (PAR1 , PAR2, and PAR4) can mediate Xa signaling in heterologous expression systems. However, other candidate Xa receptors have been described, and the extent to which one or more PARs account for Xa signaling in relevant differentiated cells is unknown. We examined Xa signaling in endothelial cells from wildtype and PAR-deficient mice. Wild-type endothelial cells responded to agonists for PAR1, PAR2, and PAR4. Relative to wild-type, Xa-triggered phosphoinositide hydrolysis was reduced by 60-75% in Par2 -/- endothelial cells, by 20-30% in Par1 -/- endothelial cells, and by ∼90% in Par2 -/- endothelial cells treated with a PAR1 antagonist. Similar results were obtained when ERK1/2 phosphorylation was used to assess Xa signaling. Thus PAR2 is the main endogenous Xa receptor in these endothelial cell preparations and, together, PAR2 and PAR1 appear to account for ∼90% of endothelial Xa signaling. By contrast, in fibroblasts, PAR1 by itself accounted for virtually all Xa-induced phosphoinositide hydrolysis. This information is critical for the design and interpretation of knockout mouse studies to probe the possible roles of Xa signaling in vivo.
AB - The coagulation protease Factor Xa (Xa)1 triggers a variety of cellular responses that may be important for inflammatory reactions to tissue injury. Protease-activated receptors (PAR1 , PAR2, and PAR4) can mediate Xa signaling in heterologous expression systems. However, other candidate Xa receptors have been described, and the extent to which one or more PARs account for Xa signaling in relevant differentiated cells is unknown. We examined Xa signaling in endothelial cells from wildtype and PAR-deficient mice. Wild-type endothelial cells responded to agonists for PAR1, PAR2, and PAR4. Relative to wild-type, Xa-triggered phosphoinositide hydrolysis was reduced by 60-75% in Par2 -/- endothelial cells, by 20-30% in Par1 -/- endothelial cells, and by ∼90% in Par2 -/- endothelial cells treated with a PAR1 antagonist. Similar results were obtained when ERK1/2 phosphorylation was used to assess Xa signaling. Thus PAR2 is the main endogenous Xa receptor in these endothelial cell preparations and, together, PAR2 and PAR1 appear to account for ∼90% of endothelial Xa signaling. By contrast, in fibroblasts, PAR1 by itself accounted for virtually all Xa-induced phosphoinositide hydrolysis. This information is critical for the design and interpretation of knockout mouse studies to probe the possible roles of Xa signaling in vivo.
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U2 - 10.1074/jbc.M108555200
DO - 10.1074/jbc.M108555200
M3 - Article
C2 - 11850418
AN - SCOPUS:0037013268
SN - 0021-9258
VL - 277
SP - 16081
EP - 16087
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 18
ER -