Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Digestive Department, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
J Cell Physiol. 2022 Aug;237(8):3369-3380. doi: 10.1002/jcp.30807. Epub 2022 Jun 8.
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.
心血管疾病（CVD）是 2 型糖尿病（T2DM）各种并发症导致的主要死亡原因。利伐沙班（Xarelto；拜耳），一种口服直接因子 Xa（FXa）抑制剂，可防止凝血级联反应在 CVD 中的激活。鉴于其抗凝和抗炎作用，我们评估了利伐沙班治疗可能减轻 T2DM 小鼠血管病变和功能障碍的假设。使用 Western blot 分析、免疫荧光染色和 RNA 干扰评估 C57BL/6、BKS-db/db、BKS-db/+、野生型（WT）和 NLRP3 小鼠的生化指标、血管病变和蛋白表达。利伐沙班对 T2DM 小鼠的血管功能障碍具有良好的保护作用，可显著缓解血管张力、内膜-中膜厚度和胶原沉积。NLR 家族吡啶结构域包含 3（NLRP3）敲除组和利伐沙班的类似改善表明，利伐沙班通过改善 NLRP3 炎性小体激活，对糖尿病小鼠的血管功能障碍具有积极作用。此外，可溶性 FXa 诱导的小鼠主动脉内皮细胞（MAECs）和平滑肌细胞（MOVASs）的炎症和细胞功能障碍可被利伐沙班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。数据表明，利伐沙班可在体内和体外阻止 T2DM 小鼠血管功能障碍和炎症的发展。利伐沙班治疗还可通过 PARs、MAPK 和 NF-κB 途径减轻 NLRP3 炎性小体的激活。本研究为利伐沙班治疗 T2DM 血管并发症提供了机制证据。
