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Abstract：
Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms.
In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration.
Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.
In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration.
Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.
摘要：
利伐沙班是静脉血栓栓塞治疗的特异性因子Xa(FXa)抑制剂。最近,越来越多的证据报道了利伐沙班对治疗冠状动脉和外周动脉疾病等心血管疾病的有益作用.然而,其对腹主动脉瘤(AAA)的潜在影响尚不清楚.本研究旨在探讨利伐沙班治疗是否可以减轻实验性AAA进展及其相关机制。
在人类动脉瘤主动脉中，FXa蛋白表达显著上调。进一步的调查发现血浆FXa水平之间存在正相关，AAA严重程度（最大主动脉直径），和动脉瘤内血栓百分比。在注射AngII(血管紧张素II)的ApoE-/-小鼠中，高剂量利伐沙班（15mg/kg/d）给药14天显着降低了最大主动脉直径，而低剂量利伐沙班（5mg/kg/d）则不具有这种保护作用。尽管利伐沙班治疗降低了AAA和血栓形成的发生率，这些差异没有达到统计学意义.免疫组织化学显示明显的主动脉重塑，包括AngII诱导的AAAs中胶原蛋白含量增加和弹性蛋白降解增强，高剂量利伐沙班治疗抑制。进一步的分析表明，利伐沙班通过减少白细胞浸润发挥其保护作用，炎性细胞因子表达，和基质金属蛋白酶（MMPs）在主动脉壁的表达。在氯化钙诱导的AAA模型中也观察到利伐沙班对动脉瘤发展的抑制作用。机械上,在人类主动脉内皮细胞中，FXa刺激增加炎性细胞因子(白细胞介素(IL)-1β,IL-6，IL-8，单核细胞趋化蛋白-1）和粘附分子，这些都被利伐沙班的共同治疗逆转了。FXa刺激后，随后的单核细胞-内皮细胞相互作用得到增强，并通过利伐沙班协同治疗得到缓解。此外,FXa诱导人主动脉内皮细胞中MMP2的表达显着升高，利伐沙班联合用药改善了这种情况。
利伐沙班减弱了血管紧张素II和氯化钙诱导的腹主动脉瘤（AAA）进展，通过抑制主动脉重塑和炎症。利伐沙班可能是通过抵消FXa诱导的主动脉壁炎症来减轻AAA发展的有前途的治疗剂。
在人类动脉瘤主动脉中，FXa蛋白表达显著上调。进一步的调查发现血浆FXa水平之间存在正相关，AAA严重程度（最大主动脉直径），和动脉瘤内血栓百分比。在注射AngII(血管紧张素II)的ApoE-/-小鼠中，高剂量利伐沙班（15mg/kg/d）给药14天显着降低了最大主动脉直径，而低剂量利伐沙班（5mg/kg/d）则不具有这种保护作用。尽管利伐沙班治疗降低了AAA和血栓形成的发生率，这些差异没有达到统计学意义.免疫组织化学显示明显的主动脉重塑，包括AngII诱导的AAAs中胶原蛋白含量增加和弹性蛋白降解增强，高剂量利伐沙班治疗抑制。进一步的分析表明，利伐沙班通过减少白细胞浸润发挥其保护作用，炎性细胞因子表达，和基质金属蛋白酶（MMPs）在主动脉壁的表达。在氯化钙诱导的AAA模型中也观察到利伐沙班对动脉瘤发展的抑制作用。机械上,在人类主动脉内皮细胞中，FXa刺激增加炎性细胞因子(白细胞介素(IL)-1β,IL-6，IL-8，单核细胞趋化蛋白-1）和粘附分子，这些都被利伐沙班的共同治疗逆转了。FXa刺激后，随后的单核细胞-内皮细胞相互作用得到增强，并通过利伐沙班协同治疗得到缓解。此外,FXa诱导人主动脉内皮细胞中MMP2的表达显着升高，利伐沙班联合用药改善了这种情况。
利伐沙班减弱了血管紧张素II和氯化钙诱导的腹主动脉瘤（AAA）进展，通过抑制主动脉重塑和炎症。利伐沙班可能是通过抵消FXa诱导的主动脉壁炎症来减轻AAA发展的有前途的治疗剂。
