Abstract 13438: Rivaroxaban, a Direct Factor Xa Inhibitor, Attenuates Neointima Formation after Mechanical Vascular Injury

Abstract

Bachground: Activated factor X (FXa) is a key member in the coagulation cascade responsible for thrombin generation, although accumulating evidence suggests it also has various biological functions in many cell types, contributing to the pathogenesis of neointima formation after vascular injury. In this study, we assessed the hypothesis that rivaroxaban, a direct FXa inhibitor, attenuates neointima formation after mechanical vascular injury by inhibiting both pro-inflammatory activation of macrophages and proliferative activation of vascular smooth muscle cells (VSMCs). Methods and Results: Rivaroxaban (5 mg/kg/day) was administered for 4 weeks to C57BL/6 mice after wire-mediated vascular injury. Plasma lipid levels and blood pressure were similar between rivaroxaban group and the control group. Rivaroxaban significantly reduced neointima area (30452 ± 2531 μm2 vs. 19582 ± 2531 μm2; P < 0.05) and intima/media ratio (4.37 ± 0.50 vs. 2.60 ± 0.50; P < 0.05) in the injured arteries at four weeks after injury, as determined by elastica van Gieson staining, compared with the control group. In vitro experiments using mouse peritoneal macrophages or murine macrophage cell line RAW264.7 demonstrated that FXa increased mRNA expression of inflammatory molecules (e.g., IL-1β and TNF-α) and vasoproliferative molecules (e.g., PDGF and BMP-2), which was blocked in the presence of rivaroxaban. In vitro experiments using rat VSMCs demonstrated that FXa stimulation promoted both mitogenesis and migration of this cell type, as determined by MTS assay and scratch-wound assay, respectively. Rivaroxaban attenuated these FXa-induced mitogenesis and migration. Conclusions: Rivaroxaban attenuates neointima formation in a mouse model of vascular injury. Our analyses suggest that FXa contributes to both pro-inflammatory activation of macrophages and proliferative activation of VSMCs, participating in the progression of neointima formation after vascular injury. FXa may serve as a potential therapeutic target for neointima formation after vascular injury.