Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction
Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction
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DOI：
10.5551/jat.48405
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发表时间：
2019-01-01
影响因子：
4.4
通讯作者：
Sakata, Yasushi
中科院分区：
文献类型：
--
作者：
Liu, Jingyi;Nishida, Makoto;Sakata, Yasushi
目的：直接口服抗凝药FXa抑制剂已应用于心肌梗死（MI）的临床治疗。小鼠实验研究表明，FXa 抑制剂可减少冠状动脉结扎后的动脉粥样硬化并预防心脏功能障碍。这些研究表明，蛋白酶激活受体 (PAR) 2（激活 FX 的主要受体）可能在动脉粥样硬化和心脏重塑中发挥重要作用。 方法：使用 SR-BI KO/ApoeR61(h/h) 小鼠（Hypo E 小鼠）在新的缺血性心肌病 (ICM) 小鼠模型中研究 FXa 抑制剂利伐沙班的作用，该小鼠因高脂饮食而发生 MI结果：在诱导 MI 后，Hypo E 小鼠被喂食含利伐沙班 (n = 49) 或对照食物 (n = 126)。与未治疗组相比，利伐沙班治疗组在心肌梗死诱发后 2 周的生存曲线显着改善（生存率：分别为 75.5% 和 47.4%，p = 0.0012）。超声心动图和 BNP 表达表明利伐沙班可减轻心力衰竭。组织学分析显示，利伐沙班可减少主动脉粥样硬化和冠状动脉闭塞，并显着减轻心脏纤维化。利伐沙班治疗可降低心脏 PAR2 水平和促炎基因。在体外，利伐沙班的应用表明心肌细胞抗缺氧的细胞活力增加，心脏成纤维细胞中缺氧诱导的炎症和纤维化相关分子减少。 PAR2 拮抗剂对抗缺氧引起的炎症的效果与心脏成纤维细胞中的利伐沙班相当。结论：Hypo E 小鼠 MI 后立即使用利伐沙班治疗，可通过减弱心脏重塑（部分通过抑制 PAR2 介导的炎症途径）来阻止 ICM 的进展。
Aim: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that protease-activated receptor (PAR) 2, a major receptor of activated FX, may play an important role in atherosclerosis and cardiac remodeling.Methods: The effects of a FXa inhibitor, rivaroxaban, were investigated in a new murine model of ischemic cardiomyopathy (ICM) using SR-BI KO/ApoeR61(h/h) mice (Hypo E mice) that developed MI by high-fat diet loading.Results: Hypo E mice were fed rivaroxaban-containing (n=49) or control chow diets (n=126) after the induction of MI. The survival curve of the rivaroxaban-treated group 2 weeks after the induction of MI was improved significantly as compared with the non-treatment group (survival rate: 75.5% vs. 47.4%, respectively, p = 0.0012). Echocardiography and the expression of BNP showed that rivaroxaban attenuated heart failure. Histological analyses revealed that rivaroxaban reduced aortic atherosclerosis and coronary occlusion, and markedly attenuated cardiac fibrosis. Rivaroxaban treatment decreased cardiac PAR2 levels and pro-inflammatory genes.In vitro, rivaroxaban application demonstrated the increase of cell viability against hypoxia in cardiac myocytes and the reduction of hypoxia-induced inflammation and fibrosis-related molecules in cardiac fibroblasts. The effects of the PAR2 antagonist against hypoxia-induced inflammation were comparable to rivaroxaban in cardiac fibroblasts.Conclusions: Rivaroxaban treatment just after MI in Hypo E mice prevented the progression of ICM by attenuating cardiac remodeling, partially through the suppression of the PAR2-mediated inflammatory pathway.