Journal of Pharmacological Sciences (Mar 2017)

Demeanor of rivaroxaban in activated/inactivated FXa

  • Kaname Seki,
  • Yosuke Mizuno,
  • Toku Sakashita,
  • Shintaro Nakano,
  • Jun Tanno,
  • Yasushi Okazaki,
  • Toshihiro Muramatsu,
  • Shigeyuki Nishimura,
  • Takaaki Senbonmatsu

DOI
https://doi.org/10.1016/j.jphs.2017.02.010
Journal volume & issue
Vol. 133, no. 3
pp. 156 – 161

Abstract

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Activated factor X (FXa) plays an important role in thrombin generation and inflammation. Factor X is not converted constitutively to FXa, but only after intrinsic clotting factors are activated and/or cellular injury occurs. Although rivaroxaban is one of direct FXa inhibitors, its function in the inactivated coagulation cascade is unclear. In human umbilical vein endothelial cells that natively express protease-activated receptor-1 and -2, high dose rivaroxaban did not alter gene transcripts including pro-inflammatory genes in DNA microarray. Upon FXa stimulation, the expressions of pro-inflammatory genes such as monocyte chemoattractant protein-1 (MCP-1), intracellular adhesion molecule-1, and interleukin-8 were maximally increased at 4 h after stimulation, and were suppressed by rivaroxaban. To confirm these results, quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) for MCP-1 were performed. FXa evoked the expression of MCP-1 maximally at 4 h after stimulation, whereas MCP-1 displayed a different temporal activation in ELISA. Interestingly, rivaroxaban inhibited both time courses of MCP-1 expression. These results suggest that rivaroxaban may not influence gene modulation in the inactivated coagulation state, but can attenuate the endothelial damage evoked by FXa and pro-inflammatory cytokine genes.

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