Rivaroxaban (Riv), a direct factor Xa (FXa) inhibitor, exerts anti-inflammatory effects in addition to anticoagulation. However, its role in cardiovascular remodeling is largely unknown. We tested the hypothesis that Riv attenuates the progression of cardiac hypertrophy and fibrosis induced by continuous activation of the renin–angiotensin system (RAS) in renin-overexpressing hypertensive transgenic (Ren-Tg) mice. We treated 12-week-old male Ren-Tg and wild-type (WT) mice with a diet containing Riv (12 mg/kg/day) or a regular diet for 4 weeks. After this, FXa in plasma significantly increased in Ren-Tg mice compared with WT mice, and Riv inhibited this increase. Left ventricular wall thickness (LVWT) and the area of cardiac fibrosis evaluated by Masson’s trichrome staining were greater in Ren-Tg mice than in WT mice, and Riv decreased them. Cardiac expression levels of the protease-activated receptor (PAR)-2, tumor necrosis factor-α, transforming growth factor (TGF)-β1, and collagen type 3 α1 (COL3A1) genes were all greater in Ren-Tg mice than in WT mice, and Riv attenuated these increases. To investigate the possible involvement of PAR-2, we treated Ren-Tg mice with a continuous subcutaneous infusion of 10 μg/kg/day of the PAR-2 antagonist FSLLRY for 4 weeks. FSLLRY significantly decreased LVWT and cardiac expression of PAR-2, TGF-β1, and COL3A1. In isolated cardiac fibroblasts (CFs), Riv or FSLLRY pretreatment inhibited the FXa-induced increase in the phosphorylation of extracellular signal-regulated kinases. In addition, Riv or FSLLRY inhibited FXa-stimulated wound closure in CFs. Riv exerts a protective effect against cardiac hypertrophy and fibrosis development induced by continuous activation of the RAS, partly by inhibiting PAR-2.

利伐沙班 (Riv) 是一种直接 Xa 因子 (FXa) 抑制剂，除抗凝外，还具有抗炎作用。然而，它在心血管重塑中的作用在很大程度上是未知的。我们检验了 Riv 减轻肾素过表达的高血压转基因 (Ren-Tg) 小鼠中肾素-血管紧张素系统 (RAS) 持续激活诱导的心脏肥大和纤维化进展的假设。我们用含有 Riv（12 mg/kg/天）的饮食或常规饮食治疗 12 周大的雄性 Ren-Tg 和野生型 (WT) 小鼠 4 周。此后，与 WT 小鼠相比，Ren-Tg 小鼠血浆中的 FXa 显着增加，而 Riv 抑制了这种增加。Ren-Tg小鼠的左心室壁厚度（LVWT）和通过Masson三色染色评估的心脏纤维化面积大于WT小鼠，Riv降低了它们。Ren-Tg 小鼠中蛋白酶激活受体 (PAR)-2、肿瘤坏死因子-α、转化生长因子 (TGF)-β1 和 3 型胶原蛋白 α1 (COL3A1) 基因的心脏表达水平均高于 WT小鼠，而 Riv 减弱了这些增加。为了研究PAR-2的可能参与，我们用10μg/kg/天的PAR-2拮抗剂FSLLRY连续皮下输注Ren-Tg小鼠4周。FSLLRY 显着降低 PAR-2、TGF-β1 和 COL3A1 的 LVWT 和心脏表达。在分离的心脏成纤维细胞 (CFs) 中，Riv 或 FSLLRY 预处理抑制了 FXa 诱导的细胞外信号调节激酶磷酸化的增加。此外，Riv 或 FSLLRY 抑制 CF 中 FXa 刺激的伤口闭合。