Journal
THROMBOSIS RESEARCH
Volume 142, Issue -, Pages 44-51Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.thromres.2016.04.008
Keywords
Dabigatran; Gene expression; Inflammatory markers; Rivaroxaban; Thrombin
Categories
Funding
- Bayer Pharma AG
- Janssen Scientific Affairs, LLC
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Introduction: In addition to its central role in coagulation, thrombin is involved in non-hemostatic activities such as inflammation. Direct inhibition of thrombin activity (e.g. with dabigatran) or reducing its generation by inhibition of Factor Xa (e.g. with rivaroxaban) may therefore have anti-inflammatory effects. Materials and Methods: Microarray experiments were performed to identify transcriptome-wide changes in mRNA expression levels induced by thrombin in the presence and absence of the PAR-1 antagonist vorapaxar in primary human umbilical vein endothelial cells (HUVECs). On this basis, HUVECs were incubated with recalcified plasma, with or without rivaroxaban (0.3-3000 nM), dabigatran (0.3-10,000 nM), or vorapaxar (0.3-10 nM). Expression levels of preselected pro-inflammatory genes were quantified by real-time PCR. Results: Vorapaxar abolished 67 of the 69 transcripts altered by more than twofold on addition of thrombin to HUVECs. ELAM-1, VCAM-1, ICAM-1, MCP-1, IL-8, CXCL1, and CXCL2 were among the genes most strongly induced by thrombin. Inflammatory gene expression after stimulation of thrombin generation was concentration-dependently suppressed by vorapaxar, dabigatran, and rivaroxaban. However, dabigatran at low concentrations (3-300 nM) increased significantly the expression levels of CXCL1, CXCL2, IL-8, ELAM-1, MCP-1, and tissue factor. Conclusion: In HUVECs, plasma-induced transcriptional changes are mediated by thrombin-induced PAR-1 activation. Rivaroxaban downregulated the expression of pro-inflammatory markers and tissue factor to a similar extent to dabigatran. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.
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