Inhibition of activated factor X by rivaroxaban attenuates neointima formation after wire-mediated vascular injury

• Published in: European journal of pharmacology Vol. 820; pp. 222 - 228
• Main Authors: Hara, Tomoya, Fukuda, Daiju, Tanaka, Kimie, Higashikuni, Yasutomi, Hirata, Yoichiro, Yagi, Shusuke, Soeki, Takeshi, Shimabukuro, Michio, Sata, Masataka
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.02.2018
• Subjects: Activated factor X; Inflammation; Macrophage; Neointima formation; Rivaroxaban; Rivaroxaban; Inflammation; Activated factor X; Neointima formation; Macrophage
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.12.037

Accumulating evidence suggests that activated factor X (FXa), a key coagulation factor, plays an important role in the development of vascular inflammation through activation of many cell types. Here, we investigated whether pharmacological blockade of FXa attenuates neointima formation after wire-mediated vascular injury. Transluminal femoral artery injury was induced in C57BL/6 mice by inserting a straight wire. Rivaroxaban (5mg/kg/day), a direct FXa inhibitor, was administered from one week before surgery until killed. At four weeks after surgery, rivaroxaban significantly attenuated neointima formation in the injured arteries compared with control (P<0.01). Plasma lipid levels and blood pressure were similar between the rivaroxaban-treated group and non-treated group. Quantitative RT-PCR analyses demonstrated that rivaroxaban reduced the expression of inflammatory molecules (e.g., IL-1β and TNF-α) in injured arteries at seven days after surgery (P<0.05, respectively). In vitro experiments using mouse peritoneal macrophages demonstrated that FXa increased the expression of inflammatory molecules (e.g., IL-1β and TNF-α), which was blocked in the presence of rivaroxaban (P<0.05). Also, in vitro experiments using rat vascular smooth muscle cells (VSMC) demonstrated that FXa promoted both proliferation and migration of this cell type (P<0.05), which were blocked in the presence of rivaroxaban. Inhibition of FXa by rivaroxaban attenuates neointima formation after wire-mediated vascular injury through inhibition of inflammatory activation of macrophages and VSMC.