Demeanor of rivaroxaban in activated/inactivated FXa.
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.
Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan.
Kaname
K
Seki
Division of Functional Genomics & Systems Medicine, Saitama Medical University Research Center for Genomic Medicine, Saitama, Japan.
Yosuke
Y
Mizuno
Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan.
Toku
T
Sakashita
Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan.
Shintaro
S
Nakano
Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan.
Jun
J
Tanno
Division of Functional Genomics & Systems Medicine, Saitama Medical University Research Center for Genomic Medicine, Saitama, Japan.
Yasushi
Y
Okazaki
Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan.
Toshihiro
T
Muramatsu
Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan.
Shigeyuki
S
Nishimura
Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan; Research Administration Center, Saitama Medical University, Saitama, Japan. Electronic address: senbont@saitama-med.ac.jp.
Takaaki
T
Senbonmatsu
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D015951:Factor Xa / Q000494:pharmacology*; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D044462:Receptors, Proteinase-Activated / Q000235:genetics; D000069552:Rivaroxaban / Q000494:pharmacology*
C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D065427:Factor Xa Inhibitors; D016209:Interleukin-8; D044462:Receptors, Proteinase-Activated; D018799:Intercellular Adhesion Molecule-1; D000069552:Rivaroxaban; D015951:Factor Xa
Activated factor X; Anticoagulant; Gene modulation; Inflammation; Rivaroxaban