Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR
Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR
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DOI：
10.1155/2019/1082497
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发表时间：
2019-01-01
影响因子：
4.6
通讯作者：
Lu, Meili
中科院分区：
文献类型：
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作者：
Leng, Bin;Zhang, Yingjie;Lu, Meili
长期暴露在高糖环境中会导致血管内皮细胞炎症，从而导致心血管疾病。黄芪甲苷(AS-IV)广泛用于心血管疾病的抗炎治疗。然而，其作用机制尚不完全清楚。在本研究中，我们观察了AS-IV对高糖诱导的内皮细胞炎症的影响，并探讨了其可能的机制。在体内，大鼠单次腹腔注射链脲佐菌素(STZ，65 mg/kg)后，灌胃给予AS-IV(40和80 mg/kg/d)，连续8周。体外培养的人脐静脉内皮细胞(HUVECs)经高糖(33 mM葡萄糖)处理后，分别加入AS-IV、NPS2143(CaSR抑制剂)、Bay 11-7082(NF-B P65抑制剂)和INF39(NLRP3抑制剂)，并用CaSR高表达慢病毒载体感染HUVECs，进一步探讨AS-IV的抗炎作用。结果显示，高糖可使IL-18、IL-1、NLRP3、caspase-1、ASC的表达增加，TLR4、核P65、CaSR的蛋白表达增加。AS-IV在体内和体外均能逆转这些变化。同时，NPS2143、Bay 11-7082和INF39在体外均能显著抑制高糖诱导的NLRP3、Asc、caspase-1、IL-18和IL-1的表达。此外，NPS2143和Bay 11-7082均可抑制高糖诱导的NLRP3、Asc、caspase-1、IL-18和IL-1的表达上调。综上所述，本研究提示AS-IV可能通过抑制TLR4/NF-B信号通路和CaSR而抑制高糖诱导的NLRP3炎性小体激活和随后的促炎细胞因子的分泌，为AS-IV的抗炎活性提供了新的见解。
Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-B p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1 (IL-1), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1 expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1 expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-B signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.