Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension
Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension
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DOI：
10.1248/bpb.b20-01011
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发表时间：
2021-05-01
影响因子：
2
通讯作者：
Hayashi, Tetsuya
中科院分区：
文献类型：
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作者：
Imano, Hideki;Kato, Ryuji;Hayashi, Tetsuya
肺动脉高压（PAH）是一种进行性疾病，经常导致右心室（RV）重塑。本研究的目的是研究利伐沙班对PAH大鼠模型（使用Sugen 5416和慢性缺氧）中RV重构的影响，以及利伐沙班对人心脏微血管内皮细胞（HCMEC）的体外影响。为了建立PAH模型，雄性Sprague-Dawley大鼠皮下注射Sugen 5416（20 mg/kg），并暴露于缺氧（10% O-2）2周，随后暴露于常氧2周。然后将动物分成2组，再给予或不给予利伐沙班（12 mg/kg/d）4周。在缺氧条件（37摄氏度、1% O-2、5% CO2）下，使用Sugen 5416以及使用或不使用利伐沙班培养HCMEC。利伐沙班可显著降低缺氧大鼠右室收缩压和富尔顿指数。在HCMEC中，Sugen 5416缺氧增加了蛋白酶激活受体-2（PAR-2）的表达以及细胞外信号调节激酶（ERK）、c-Jun N-末端激酶（JNK）和核因子-κ B（NF-κ B）的磷酸化，而利伐沙班治疗显著抑制了这些蛋白的表达。利伐沙班通过降低ERK、JNK和NF-κ B活化来减轻PAH大鼠模型中的RV重构。利伐沙班有可能对PAH患者的RV重塑产生叠加效应。
Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O-2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 degrees C, 1% O-2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-kappa B), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-kappa B activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.