Z-guggulsterone regulates MDR1 expression mainly through the pregnane X receptor-dependent manner in human brain microvessel endothelial cells
Z-guggulsterone regulates MDR1 expression mainly through the pregnane X receptor-dependent manner in human brain microvessel endothelial cells
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Z-guggulsterone主要通过孕烷X受体依赖性方式调节人脑微血管内皮细胞中MDR1的表达
DOI：
10.1016/j.ejphar.2020.173023
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发表时间：
2020-05-05
影响因子：
5
通讯作者：
Kong，Ping-shi
中科院分区：
文献类型：
--
作者：
Xu，Hong-Bin;Tang，Zhao-Qi;Kong，Ping-shi
近年来研究发现，人脑微血管内皮细胞中存在着多药耐药蛋白1（MDR 1）的表达，并与PXR协同作用。本研究旨在探讨Z-麦角甾酮对人脑微血管内皮细胞MDR 1的调控作用，并探讨其是否参与PXR的调节。结果显示，Z-guggulsterone（30 μM）在24 h时可同时抑制人脑源性微血管内皮细胞（hBDMECs）PXR和MDR 1的表达。同时，转染PXR siRNA的hBDMECs中PXR和MDR 1的表达水平同时降低;转染MDR-1 siRNA的hBDMECs中MDR 1的表达显著降低，而PXR的表达无明显变化。此外，Z-guggulsterone通过减少cAMP/PKA的释放，抑制hBDMECs PXR的活化。Z-guggulsterone可降低hBDMECs中共激活因子SRC-1的表达，从而抑制MDR 1基因转录的激活。此外，Z-guggulsterone（30 μM）作用24 h可显著抑制hBDMECs中人组成型雄甾烷受体（CAR）蛋白的表达。然而，用Z-guggulsterone（≤30 μM）处理后，人PXR转染细胞中的MDR 1报告基因活性水平低于人CAR转染细胞。随着人PXR/CAR比例的增加，Z-麦角甾酮对MDR 1报告基因激活的抑制作用逐渐增强，其抑制作用大于人CAR/hPXR比例的增加。本研究提示Z-麦角甾酮可能主要通过PXR依赖的方式下调hBDMECs的外排功能和MDR 1的表达。
Recently studies showed that pregnane X receptor (PXR) was expressed in human brain microvessel endothelial cells and coordinately induced multidrug resistance protein 1 (MDR1) expression. The present study aimed to investigate the regulatory effect of Z-guggulsterone on MDR1 in human brain microvessel endothelial cells, and explored whether it involved modulation of PXR. The results showed that Z-guggulsterone (30 μM) simultaneously inhibited the expression of PXR and MDR1 at 24 h in human brain-derived microvessel endothelial cells (hBDMECs). Meanwhile, the levels of PXR and MDR1 expression were simultaneously reduced in PXR siRNA-transfected hBDMECs; MDR-1 siRNA-transfected hBDMECs showed significant decrease in MDR1 expression, but no change in PXR expression. Furthermore, Z-guggulsterone inhibited the activation of PXR in hBDMECs through decreasing the release of cAMP/PKA. Z-guggulsterone reduced the co-activator SRC-1 expression in hBDMECs, as to prevent the activation of MDR1 gene transcription. In addition, Z-guggulsterone (30 μM) at 24 h significantly inhibited the expression of human constitutive androstane receptor (CAR) protein in hBDMECs. However, after treatment with Z-guggulsterone (≤30 μM), the level of MDR1 reporter gene activity was lower in human PXR-transfected cells than that in human CAR-transfected cells. The inhibition effect of Z-guggulsterones on MDR1 reporter gene activation was gradually enhanced with the increase of human PXR to CAR ratio, which was greater extent than that with the increase of human CAR to hPXR ratio. The present study suggested that Z-guggulsterone down-regulating the efflux function and expression of MDR1 in hBDMECs might be mainly through the PXR-dependent manner.