Favorable effect of rivaroxaban against vascular dysfunction in diabetic mice by inhibiting NLRP3 inflammasome activation
Favorable effect of rivaroxaban against vascular dysfunction in diabetic mice by inhibiting NLRP3 inflammasome activation
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DOI：
10.1002/jcp.30807
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发表时间：
2022-06
影响因子：
5.6
通讯作者：
Qing Li;Xin Yang;Wei Wei-Wei;Xiang‐peng Hu;Xiao‐xue Li;Ming Xu
中科院分区：
文献类型：
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作者：
Qing Li;Xin Yang;Wei Wei-Wei;Xiang‐peng Hu;Xiao‐xue Li;Ming Xu
心血管疾病（CVD）是2型糖尿病（T2 DM）各种并发症的主要死亡原因。利伐沙班（拜瑞妥;拜耳）是一种口服直接Xa因子（FXa）抑制剂，可防止CVD中凝血级联反应的激活。考虑到其抗凝和抗炎作用，我们评估了利伐沙班治疗可能减轻T2 DM小鼠血管病变和功能障碍的假设。C57 BL/6、BKS-db/db、BKS-db/+、野生型（WT）和NLRP 3-/-小鼠喂食标准饲料或高脂饮食（HFD）。生化指标，血管病变，蛋白质表达采用Western印迹分析，免疫荧光染色，RNA干扰。利伐沙班对T2 DM小鼠的血管功能障碍具有良好的保护作用，血管张力、内膜中层厚度和胶原沉积显著减轻。在NLR家族pyrin结构域3（NLRP 3）敲除组和利伐沙班中的类似改善指出利伐沙班通过改善NLRP 3炎性体活化而对糖尿病小鼠中的血管功能障碍具有积极作用。此外，利伐沙班可通过蛋白酶激活受体（PAR-1、PAR-2）、丝裂原激活蛋白激酶（MAPK）和核因子κ-B（NF-κB）途径阻断可溶性FXa诱导的小鼠主动脉内皮细胞（MAEC）和平滑肌细胞（MOVAS）炎症和细胞功能障碍的增加。这些数据表明，利伐沙班在体内和体外可阻断T2 DM小鼠中血管功能障碍和炎症的发展。利伐沙班治疗还可通过PAR、MAPK和NF-κB途径减弱NLRP 3炎性体活化。本研究提供了利伐沙班治疗T2 DM血管并发症的机制证据。
Cardiovascular disease (CVD) is the leading cause of death in various complications of type 2 diabetes mellitus (T2DM). Rivaroxaban (Xarelto; Bayer), an oral direct factor Xa (FXa) inhibitor, prevents the activation of the coagulation cascade in CVD. Considering its anticoagulant and anti‐inflammatory effects, we assessed the hypothesis that rivaroxaban treatment may attenuate the vascular lesion and dysfunction in T2DM mice. C57BL/6, BKS‐db/db, BKS‐db/+, wild‐type (WT), and NLRP3−/− mice were fed with standard chow or high‐fat diet (HFD). Biochemical indexes, vascular lesions, and protein expression were evaluated using Western blot analysis, immunofluorescent staining, and RNA interference. Rivaroxaban presented favorable protection of vascular dysfunction in T2DM mice with significantly relieved vascular tension, intima‐media thickness, and collagen deposition. Similar improvements in NLR family pyrin domain containing 3 (NLRP3) knockout groups and rivaroxaban pointed to the positive role of rivaroxaban against vascular dysfunction in diabetic mice by ameliorating NLRP3 inflammasome activation. Furthermore, the augmentation of inflammation and cell dysfunction in mice aortic endothelial cells (MAECs) and smooth muscle cells (MOVASs) induced by soluble FXa may be blocked by rivaroxaban via protease‐activated receptors (PAR‐1, PAR‐2), mitogen‐activated protein kinase (MAPK), and nuclear factor κ‐B (NF‐κB) pathway. The data indicate that the development of vascular dysfunction and inflammation in T2DM mice may be blocked by rivaroxaban in vivo and in vitro. Rivaroxaban treatment may also attenuate NLRP3 inflammasome activation via PARs, MAPK, and NF‐κB pathway. This study provides mechanistic evidence of rivaroxaban therapies for vascular complications of T2DM.