title: Expression of pro-inflammatory genes in human endothelial cells: Comparison of rivaroxaban and dabigatran.
abstract: BACKGROUND
  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.
  
  
  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 (0.3-3000nM), dabigatran (0.3-10,000nM), or vorapaxar (0.3-10nM). 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 (3-300nM) increased significantly the expression levels of CXCL1, CXCL2, IL-8, ELAM-1, MCP-1, and tissue factor.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Global Biomarkers Research, Bayer Pharma AG, Wuppertal, Germany. Electronic address: peter.ellinghaus@bayer.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Ellinghaus
authors.affiliation: Formerly Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany. Electronic address: elisabeth.perzborn@bayer.com.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perzborn
authors.affiliation: Global Biomarkers Research, Bayer Pharma AG, Wuppertal, Germany. Electronic address: peter.hauenschild@bayer.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Hauenschild
authors.affiliation: Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany. Electronic address: christoph.gerdes@bayer.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gerdes
authors.affiliation: Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany. Electronic address: stefan.heitmeier@bayer.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heitmeier
authors.affiliation: Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany. Electronic address: mayken.visser@bayer.com.
authors.forename: Mayken
authors.initials: M
authors.lastname: Visser
authors.affiliation: Lead Generation & Optimization, Bayer Pharma AG, Wuppertal, Germany. Electronic address: holger.summer@bayer.com.
authors.forename: Holger
authors.initials: H
authors.lastname: Summer
authors.affiliation: Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany. Electronic address: volker.laux@bayer.com.
authors.forename: Volker
authors.initials: V
authors.lastname: Laux
mesh_terms: D000991:Antithrombins / Q000494:pharmacology*; D000069604:Dabigatran / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D007783:Lactones / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000276:immunology; D000069552:Rivaroxaban / Q000494:pharmacology*; D013917:Thrombin / Q000276:immunology*; D059467:Transcriptome / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors
chemical_list: D000991:Antithrombins; D065427:Factor Xa Inhibitors; D007783:Lactones; D011725:Pyridines; D044463:Receptor, PAR-1; D000069552:Rivaroxaban; D013917:Thrombin; D000069604:Dabigatran; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors
keywords: Dabigatran; Gene expression; Inflammatory markers; Rivaroxaban; Thrombin