Expression of pro-inflammatory genes in human endothelial cells: Comparison of rivaroxaban and dabigatran. Issue 142 (June 2016)

• Record Type: Journal Article
• Authors: Ellinghaus, Peter; Perzborn, Elisabeth; Hauenschild, Peter; Gerdes, Christoph; Heitmeier, Stefan; Visser, Mayken; Summer, Holger; Laux, Volker
• Is Part Of: Thrombosis research. Issue 142(2016)
• Page Start: 44
• Page End: 51
• Publication Date: 2016-06
• Subjects: ACTB cytosolic β-actin -- APC activated protein C -- B2M β-2-microglobulin -- CXCL chemokine (C-X-C motif) ligand -- MCP chemokine (C-C motif) ligand -- DMSO dimethyl sulfoxide -- ELAM endothelial leukocyte adhesion molecule -- EBM endothelial cell basal medium -- HUVEC human umbilical vein endothelial cell -- ICAM intercellular adhesion molecule -- IL interleukin -- MMP matrix metalloproteinase -- ANOVA one-way analysis of variance -- PC protein C -- PAR proteinase-activated receptor -- RFI relative fluorescence intensity -- TM thrombomodulin -- TF tissue factor -- TNF tumor necrosis factor -- VCAM vascular cell adhesion molecule; Dabigatran -- Gene expression -- Inflammatory markers -- Rivaroxaban -- Thrombin; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2016.04.008
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: 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. Highlights: Thrombin-induced PAR-1 activation mediates inflammatory gene expression in HUVECs. Rivaroxaban and dabigatran downregulated the expression of pro-inflammatory markers. Low concentrations of dabigatran (3–300 nM) increased inflammatory gene expression. Dabigatran at low concentrations showed a transient increase in thrombin activity.