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Published online before print January 17, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070347

Accepted for publication November 1, 2007.

Article

Factor Xa Stimulates Proinflammatory and Profibrotic Responses in Fibroblasts via Protease-Activated Receptor-2 Activation

Keren Borensztajn*{dagger}@, Jurriën Stiekema{dagger}, Sebastiaan Nijmeijer{dagger}, Pieter H. Reitsma{dagger}, Maikel P. Peppelenbosch*, and C. Arnold Spek{dagger}

From the Department of Cell Biology,* University of Groningen, Groningen; and the Center for Experimental and Molecular Medicine,{dagger} Academic Medical Center, Amsterdam, The Netherlands

@ To whom correspondence should be addressed. E-mail: k.s.borensztajn{at}amc.uva.nl.


  Abstract

Coagulation proteases have been suggested to play a role in the pathogenesis of tissue remodeling and fibrosis. We therefore assessed the proinflammatory and fibroproliferative effects of coagulation protease factor (F)Xa. We show that FXa elicits a signaling response in C2C12 and NIH3T3 fibroblasts. FXa-induced ERK1/2 phosphorylation was dependent on protease-activated receptor (PAR)-2 cleavage because desensitization with a PAR-2 agonist (trypsin) but not a PAR-1 agonist (thrombin) abolished FXa-induced signal transduction and PAR-2 siRNA abolished FXa-induced ERK1/2 phosphorylation. The PAR-2-dependent cellular effects of FXa led to fibroblast proliferation, migration, and differentiation into myofibroblasts, as demonstrated by the expression of {alpha}-smooth muscle actin and desmin, followed by the secretion of the cytokines monocyte chemotactic protein-1 and interleukin-6 as well as the expression of the fibrogenic proteins transforming growth factor-{beta} and fibronectin. To assess the relevance of FXa-induced proliferation and cell migration, we examined the effect of FXa in a wound scratch assay. Indeed, FXa facilitated wound healing in a PAR-2- and ERK1/2-dependent manner. Taken together, these results support the notion that, beyond its role in coagulation, FXa-dependent PAR-2 cleavage might play a role in the progression of tissue fibrosis and remodeling.






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Copyright © 2008 by the American Society for Investigative Pathology.