title: 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.
  
  
  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: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Tomoya
authors: T
authors: Hara
authors: Department of Cardio-Diabetes Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. Electronic address: daiju.fukuda@tokushima-u.ac.jp.
authors: Daiju
authors: D
authors: Fukuda
authors: Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan.
authors: Kimie
authors: K
authors: Tanaka
authors: Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan.
authors: Yasutomi
authors: Y
authors: Higashikuni
authors: Department of Pediatrics, The University of Tokyo Hospital, Tokyo, Japan.
authors: Yoichiro
authors: Y
authors: Hirata
authors: Department of Nutrition and Metabolism, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Sachiko
authors: S
authors: Nishimoto
authors: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Shusuke
authors: S
authors: Yagi
authors: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Hirotsugu
authors: H
authors: Yamada
authors: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Takeshi
authors: T
authors: Soeki
authors: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Tetsuzo
authors: T
authors: Wakatsuki
authors: Department of Cardio-Diabetes Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Michio
authors: M
authors: Shimabukuro
authors: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. Electronic address: masataka.sata@tokushima-u.ac.jp.
authors: Masataka
authors: M
authors: Sata
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001013:Aorta, Thoracic / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics; D001794:Blood Pressure; D002460:Cell Line; D018450:Disease Progression; D065427:Factor Xa Inhibitors / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000188:drug therapy*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics; D044464:Receptor, PAR-2 / Q000235:genetics; D000069552:Rivaroxaban / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; D065427:Factor Xa Inhibitors; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; C045069:factor X receptors; D000069552:Rivaroxaban; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Activated factor X; Atherosclerosis; Coagulation; Inflammation; Macrophages; Rivaroxaban