Hara Tomoya, Fukuda Daiju, Tanaka Kimie, Higashikuni Yasutomi, Hirata Yoichiro, Nishimoto Sachiko, Yagi Shusuke, Yamada Hirotsugu, Soeki Takeshi, Wakatsuki Tetsuzo, Shimabukuro Michio, Sata Masataka
Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Department of Cardio-Diabetes Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Atherosclerosis. 2015 Oct;242(2):639-46. doi: 10.1016/j.atherosclerosis.2015.03.023. Epub 2015 Mar 19.
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.
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.
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.
活化的凝血因子X（FXa）在凝血级联反应中起关键作用，而越来越多的证据表明，它也参与了血管系统慢性炎症的病理生理过程。在本研究中，我们评估了直接FXa抑制剂利伐沙班（Riv）通过减少巨噬细胞活化来抑制动脉粥样硬化发生的假说。
与野生型小鼠相比，载脂蛋白E缺陷（ApoE(-/-)）小鼠主动脉中FXa的受体PAR-1和PAR-2的表达水平升高（分别为P < 0.01，P < 0.05）。对8周龄的ApoE(-/-)小鼠给予利伐沙班（5 mg/kg/天），持续20周，与未治疗组相比，经苏丹IV正面染色测定，主动脉弓处动脉粥样硬化病变进展减缓（P < 0.05），且血浆脂质水平和血压无变化。组织学分析表明，利伐沙班显著减少了主动脉根部动脉粥样硬化斑块中的脂质沉积、胶原流失、巨噬细胞聚集和基质金属蛋白酶-9（MMP-9）表达。使用腹主动脉进行的定量RT-PCR分析显示，利伐沙班显著降低了炎症分子如MMP-9、肿瘤坏死因子-α（TNF-α）的mRNA表达。使用小鼠腹腔巨噬细胞或小鼠巨噬细胞系RAW264.7进行的体外实验表明，FXa增加了炎症分子（如白细胞介素（IL）-1β和TNF-α）的mRNA表达，而在有利伐沙班存在的情况下这种增加被阻断。
利伐沙班可减轻ApoE(-/-)小鼠动脉粥样硬化斑块的进展和不稳定，至少部分是通过抑制巨噬细胞的促炎活化。这些结果表明，利伐沙班除了具有抗血栓活性外，可能对动脉粥样硬化疾病的治疗特别有益。
