Baicalin alleviates hyperglycemia-induced endothelial impairment via Nrf2
Baicalin alleviates hyperglycemia-induced endothelial impairment via Nrf2
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黄芩苷通过 Nrf2 减轻高血糖引起的内皮损伤
DOI：
10.1530/joe-18-0457
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Jin, Litai
中科院分区：
文献类型：
--
作者：
Chen, Gen;Chen, Xiangjuan;Jin, Litai
黄芩苷是中草药黄芩中的主要成分，具有较强的抗炎、抗病毒和抗肿瘤活性。本工作致力于阐明黄芩苷对糖尿病引起的氧化损伤、炎症和内皮功能障碍的保护作用的分子和细胞机制。用链脲佐菌素(STZ)诱导糖尿病小鼠，用黄芩苷腹腔注射治疗。人脐静脉内皮细胞(HUVECs)分别在正常葡萄糖(NG，5.5 mM)和高糖(HG，33 mM)培养液中培养72 h，观察到黄芩苷对高血糖所致的HUVECs和糖尿病血管的氧化损伤和炎症反应有明显的抑制作用，并能恢复高血糖损伤的核因子(红系)样2(NRF2)途径的活性。然而，在转导shRNA的HUVEC中，黄芩苷对Nrf2的保护作用几乎完全消失，但不能完全消除无义shRNA转导的HUVEC对Nrf2的保护作用。机制研究表明，HG降低Akt和GSK3B的磷酸化，抑制Fyn的核输出和Nrf2的核定位，钝化Nrf2下游的靶基因，从而诱导HUVECs的氧化应激。然而，在HUVEC中，黄芩苷能很好地阻止这些破坏性的级联反应。此外，LY294002和ML385(PI3K和Nrf2的抑制剂)减弱了黄芩苷介导的Nrf2的激活和促进体内和体外血管生成的能力。综上所述，黄芩苷在高血糖状态下的内皮保护作用可能部分归因于其通过Akt/GSK3B/Fyn介导的Nrf2活化而下调ROS和炎症。
Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine, which exhibits strong anti-inflammatory, anti-viral and anti-tumor activities. The present work was devoted to elucidate the molecular and cellular mechanisms underlying the protective effects of Baicalin against diabetes-induced oxidative damage, inflammation and endothelial dysfunction. Diabetic mice, induced by streptozotocin (STZ), were treated with intraperitoneal Baicalin injections. Human umbilical vein endothelial cells (HUVECs) were cultured either in normal glucose (NG, 5.5 mM) or high glucose (HG, 33 mM) medium in the presence or absence of Baicalin for 72 h. We observed an obvious inhibition of hyperglycemia-triggered oxidative damage and inflammation in HUVECs and diabetic aortal vasculature by Baicalin, along with restoration of hyperglycemia-impaired nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway activity. However, the protective effects of Baicalin almost completely abolished in HUVECs transduced with shRNA against Nrf2, but not with nonsense shRNA. Mechanistic studies demonstrated that HG decreased Akt and GSK3B phosphorylation, restrained nuclear export of Fyn and nuclear localization of Nrf2, blunted Nrf2 downstream target genes and subsequently induced oxidative stress in HUVECs. However, those destructive cascades were well prevented by Baicalin in HUVECs. Furthermore, LY294002 and ML385 (inhibitor of PI3K and Nrf2) attenuated Baicalin-mediated Nrf2 activation and the ability of facilitates angiogenesis in vivo and ex vivo. Taken together, the endothelial protective effect of Baicalin under hyperglycemia condition could be partly attributed to its role in downregulating reactive oxygen species (ROS) and inflammation via the Akt/GSK3B/Fyn-mediated Nrf2 activation.