کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6000521 | 1579201 | 2016 | 8 صفحه PDF | دانلود رایگان |
- 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 (3-300Â nM) increased inflammatory gene expression.
- Dabigatran at low concentrations showed a transient increase in thrombin activity.
IntroductionIn 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 MethodsMicroarray 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 (0.3-3000Â nM), dabigatran (0.3-10,000Â nM), or vorapaxar (0.3-10Â nM). Expression levels of preselected pro-inflammatory genes were quantified by real-time PCR.ResultsVorapaxar 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 (3-300Â nM) increased significantly the expression levels of CXCL1, CXCL2, IL-8, ELAM-1, MCP-1, and tissue factor.ConclusionIn 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.
Journal: Thrombosis Research - Volume 142, June 2016, Pages 44-51