Abstract 16099: Rivaroxaban, A Novel Oral Anticoagulant, Attenuates Plaque Progression in ApoE-Deficient Mice Through the Inhibition of Pro-Inflammatory Activation of Macrophages
Background: Accumulating evidence suggests that activated factor X (FXa) plays an important role not only in the coagulation cascade responsible for thrombin generation, but also inflammatory responses in many cell types, contributing to the pathogenesis of metabolic syndrome and/or atherosclerosis. In this study, we assessed the hypothesis that rivaroxaban, a direct FXa inhibitor, attenuates plaque progression by inhibiting macrophage activation.
Methods and Results: Rivaroxaban (5 mg/kg/day) was administered for 20 weeks to 8-week-old apolipoprotein E-deficient (ApoE-/-) mice fed a western-type diet. There were no differences in plasma total cholesterol, triglycerides, and HDL-cholesterlol levels between the groups. Rivaroxaban significantly reduced atherosclerosis lesion progression as determined by en-face Sudan IV staining in thoracic aorta compared to control mice (16.8±0.9% vs. 21.0±1.2%; P<0.05). Quantitative RT-PCR using abdominal aorta revealed that rivaroxaban treatment reduced mRNA expression of inflammatory mediators, such of MMP-9. In vitro experiments using murine macrophage cell line RAW264.7 demonstrated that FXa with TNF-α stimulation increased mRNA expression of inflammatory molecules (e.g., MCP-1 and MMP-9) compared with non-stimulated control or TNF-α-stimulated control (P<0.05). Rivaroxaban inhibited up-regulation of these inflammatory molecules (P<0.05). Furthermore, an agonist peptide for protease-activated receptor (PAR)-2, one of the major receptors of FXa, but not for PAR-1, promoted these inflammatory molecule expression in this cell type (P<0.05).
Conclusion: Rivaroxaban attenuates atherosclerotic plaque progression and inhibits the expression of inflammatory mediators in ApoE-/- mice. Our analyses suggest that FXa-PAR2 pathway contributes to pro-inflammatory activation of macrophages at least partially.
- © 2013 by American Heart Association, Inc.