Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice.

Abstract

OBJECTIVE:

Activated factor X (FXa) plays a key role in the coagulation cascade, whereas accumulating evidence suggests that it also contributes to the pathophysiology of chronic inflammation on the vasculature. In this study, we assessed the hypothesis that rivaroxaban (Riv), a direct FXa inhibitor, inhibits atherogenesis by reducing macrophage activation.

METHODS AND RESULTS:

Expression levels of PAR-1 and PAR-2, receptors for FXa, increased in the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice compared with wild-type mice (P < 0.01, P < 0.05, respectively). Administration of Riv (5 mg/kg/day) for 20 weeks to 8-week-old ApoE(-/-) mice reduced atherosclerotic lesion progression in the aortic arch as determined by en-face Sudan IV staining compared with the non-treated group (P < 0.05) without alteration of plasma lipid levels and blood pressure. Histological analyses demonstrated that Riv significantly decreased lipid deposition, collagen loss, macrophage accumulation and matrix metallopeptidase-9 (MMP-9) expression in atherosclerotic plaques in the aortic root. Quantitative RT-PCR analyses using abdominal aorta revealed that Riv significantly reduced mRNA expression of inflammatory molecules, such as MMP-9, tumor necrosis factor-α (TNF-α). 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., interleukin (IL)-1β and TNF-α), which was blocked in the presence of Riv.

CONCLUSIONS:

Riv attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice, at least in part by inhibiting pro-inflammatory activation of macrophages. These results indicate that Riv may be particularly beneficial for the management of atherosclerotic diseases, in addition to its antithrombotic activity.

• Authors: Tomoya Hara, Daiju Fukuda, Kimie Tanaka, Yasutomi Higashikuni, Yoichiro Hirata, Sachiko Nishimoto, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Michio Shimabukuro, Masataka Sata
• Journal: Atherosclerosis (Atherosclerosis) Vol. 242 Issue 2 Pg. 639-46 (Oct 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 25817329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Anticoagulants
• Apolipoproteins E
• Factor Xa Inhibitors
• Platelet Membrane Glycoproteins
• RNA, Messenger
• Receptor, PAR-1
• Receptor, PAR-2
• factor X receptors
• Rivaroxaban
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Anticoagulants (administration & dosage)
• Aorta (metabolism, pathology)
• Aorta, Thoracic (pathology)
• Apolipoproteins E (genetics)
• Atherosclerosis (genetics)
• Blood Pressure
• Cell Line
• Disease Progression
• Factor Xa Inhibitors (chemistry)
• Human Umbilical Vein Endothelial Cells
• Humans
• Immunohistochemistry
• Inflammation
• Macrophages (metabolism)
• Male
• Matrix Metalloproteinase 9 (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Plaque, Atherosclerotic (blood, drug therapy)
• Platelet Membrane Glycoproteins (genetics)
• RNA, Messenger (metabolism)
• Receptor, PAR-1 (genetics)
• Receptor, PAR-2 (genetics)
• Rivaroxaban (administration & dosage)