Vascular endothelial dysfunction is associated with increased mortality in patients with diabetes. Astragaloside IV (As-IV) is a bioactive saponin with therapeutic potential as an anti-inflammatory and antiendothelial dysfunction. However, the underlying mechanism for how As-IV ameliorated endothelial dysfunction is still unclear. Therefore, in this study, we examined the protective effect of As-IV against endothelial dysfunction and explored potential molecular biology mechanism. In vivo, rats were intraperitoneally injected with streptozotocin (STZ) at a dose of 65 mg/kg body weight to establish a diabetic model. In vitro studies, rat aortic endothelial cells (RAOEC) were pretreated with As-IV, SB203580 (p38 MAPK inhibitor) for 2 h prior to the addition of high glucose (33 mM glucose). Our findings indicated that As-IV improved impaired endothelium-dependent relaxation and increased the levels of endothelial NO synthase (eNOS) and nitric oxide (NO) both in vivo and in vitro. Besides, As-IV treatment inhibited the elevated inflammation and oxidative stress in diabetic model both in vivo and in vitro. Moreover, As-IV administration reversed the upregulated expression of P2X7R and p-p38 MAPK in vivo and in vitro. Additionally, the effects of both P2X7R siRNA and SB203580 on endothelial cells were similar to As-IV. Collectively, our study demonstrated that As-IV rescued endothelial dysfunction induced by high glucose via inhibition of P2X7R dependent p38 MAPK signaling pathway. This provides a theoretical basis for the further study of the vascular endothelial protective effects of As-IV.

中文翻译：

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黄芪甲苷IV通过抑制P2X7R依赖性P38 MAPK信号通路对高糖诱导的内皮功能障碍的保护作用

血管内皮功能障碍与糖尿病患者的死亡率增加有关。黄芪甲苷IV（As-IV）是一种具有生物活性的皂苷，具有治疗炎症和抗内皮功能障碍的潜力。然而，As-IV如何改善内皮功能障碍的潜在机制仍不清楚。因此，在这项研究中，我们检查了As-IV对内皮功能障碍的保护作用，并探讨了潜在的分子生物学机制。在体内，以65 mg / kg体重的剂量腹膜内注射大鼠链脲佐菌素（STZ）以建立糖尿病模型。体外研究显示，在添加高葡萄糖（33 mM葡萄糖）之前，先用As-IV，SB203580（p38 MAPK抑制剂）预处理大鼠主动脉内皮细胞（RAOEC）2小时。我们的发现表明，As-IV可以改善体内和体外内皮受损的舒张功能，并增加内皮一氧化氮合酶（eNOS）和一氧化氮（NO）的水平。此外，As-IV治疗在体内和体外均抑制了糖尿病模型中炎症的升高和氧化应激。此外，As-IV给药可在体内和体外逆转P2X7R和p-p38 MAPK的上调表达。另外，P2X7R siRNA和SB203580对内皮细胞的作用均类似于As-IV。总体而言，我们的研究表明，As-IV通过抑制P2X7R依赖的p38 MAPK信号通路来挽救高糖诱导的内皮功能障碍。这为进一步研究As-IV的血管内皮保护作用提供了理论依据。