Department of Endocrinology and Metabolism, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
Phytomedicine. 2023 Apr;112:154667. doi: 10.1016/j.phymed.2023.154667. Epub 2023 Jan 12.
BACKGROUND: Oxidative stress and chronic non-infectious inflammation caused vascular endothelial dysfunction (VED) is a critical and initiating factor in Type 2 diabetes induced vascular complications, while macrophage polarization plays a regulatory role in VED. Astragalus polysaccharide (APS) has been widely used for treating diabetic vascular diseases, but its mechanisms of action have not been fully elucidated. PURPOSE: This study aimed to investigate the modulatory effects of APS on macrophage polarization and to reveal the potential mechanisms of APS in LPS and HG stimulated macrophages and diabetic model rats. METHODS: In vitro and in vivo studies were used to explore the mechanism of APS. The macrophage polarization and reactive oxygen species (ROS) release was monitored by flow cytometry and the associated inflammatory factors were detected by ELISA. For oxidative stress regulatory pathway detection, protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1 (HO-1) was measured by Western blotting. The vascular endothelial functions were measured by transwell, tube formation assay, scratch assay, adhesion assay. The thoracic aorta pathological changes were evaluated by Haematoxylin-eosin and immunohistochemistry. RESULTS: In vitro, APS inhibited the LPS/HG-stimulated THP-1 macrophage differentiated into macrophage M1, coupling with reduction in the ROS production and pro-inflammatory factors (TNF-α, IL-6, IL-12) release. Furthermore, endothelial cells proliferation and apoptosis were ameliorated after APS treatment. Meanwhile, APS-treated THP-1/macrophage occurred a differentiation into M2 polarization and anti-inflammatory factors (IL-4, IL-10, and Arg-1) release via enhancing Nrf2/HO-1 signaling pathway, which could be disturbed by using siNrf2. APS promoted the migration and angiogenesis of endothelial cells in co-cultured of HUVECs and macrophages under high glucose. Finally, similar results were observed in vivo, APS alleviated thoracic aorta complications of diabetic rats accompanied by a remarkable reduction in inflammation and an increased in the number of anti-inflammatory macrophage polarization. CONCLUSION: Our results demonstrated that APS ameliorated vascular endothelial dysfunction in diabetes by stimulating macrophage polarization to M2 via enhancing the Nrf2/HO-1 pathway.
背景：氧化应激和慢性非传染性炎症导致血管内皮功能障碍（VED）是 2 型糖尿病引起血管并发症的关键和起始因素，而巨噬细胞极化在 VED 中起调节作用。黄芪多糖（APS）已广泛用于治疗糖尿病血管疾病，但作用机制尚未完全阐明。
目的：本研究旨在探讨 APS 对巨噬细胞极化的调节作用，并揭示 APS 在 LPS 和 HG 刺激的巨噬细胞和糖尿病模型大鼠中的潜在机制。
方法：采用体外和体内研究方法探讨 APS 的作用机制。通过流式细胞术监测巨噬细胞极化和活性氧（ROS）释放，通过 ELISA 检测相关炎症因子。为了检测氧化应激调节途径，通过 Western blot 测定核因子红细胞 2 相关因子 2（Nrf2）和血红素加氧酶-1（HO-1）的蛋白表达。通过 Transwell、管形成试验、划痕试验和粘附试验测量血管内皮功能。通过苏木精-伊红和免疫组织化学评估胸主动脉病理变化。
结果：体外实验中，APS 抑制 LPS/HG 刺激的 THP-1 巨噬细胞分化为 M1 型巨噬细胞，同时减少 ROS 产生和促炎因子（TNF-α、IL-6、IL-12）释放。此外，APS 处理后内皮细胞增殖和凋亡得到改善。同时，APS 处理的 THP-1/巨噬细胞通过增强 Nrf2/HO-1 信号通路向 M2 极化分化，并释放抗炎因子（IL-4、IL-10 和 Arg-1），这一过程可被 siNrf2 干扰。APS 在高糖环境下促进共培养的 HUVECs 和巨噬细胞中内皮细胞的迁移和血管生成。最后，在体内实验中也观察到了类似的结果，APS 缓解了糖尿病大鼠的胸主动脉并发症，同时炎症明显减少，抗炎性巨噬细胞极化增加。
结论：我们的研究结果表明，APS 通过增强 Nrf2/HO-1 通路刺激巨噬细胞向 M2 极化，改善糖尿病中的血管内皮功能障碍。
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