Ginkgolide B protects human umbilical vein endothelial cells against xenobiotic injuries via PXR activation

Aim： Pregnane X receptor （PXR） is a nuclear receptor that regulates a number of genes encoding drug metabolism enzymes and transporters and plays a key role in xeno- and endobiotic detoxification. Ginkgolide B has shown to increase the activity of PXR. Here we examined whether ginkgolide B activated PXR and attenuated xenobiotic-induced injuries in endothelial cells. Methods： Human umbilical vein endothelial cells （HUVECs） were treated with ginkgolide B. The expression of PXR, CYP3A4, MDR1, VCAM-1, E-selectin and caspase-3 were quantified with qRT-PCR and Western blot analysis. Cell apoptosis was analyzed with flow cytometry. Fluorescently labeled human acute monocytic leukemia cells （THP-1 cells） were used to examine cell adhesion. Results： Ginkgolide B （30-300 pmol/L） did not change the mRNA and protein levels of PXR in the cells, but dose-dependently increased nuclear translocation of PXR protein. Ginkgolide B increased the expression of CYP3A4 and MDR1 in the cells, which was partially reversed by pretreatment with the selective PXR signaling antagonist sulforaphane, or transfection with PXR siRNA. Functionally, ginkgolide B dose-dependently attenuated doxorubicin- or staurosporine-induced apoptosis, which was reversed by transfection with PXR siRNA. Moreover, ginkgolide B suppressed TNF-a-induced THP-1 cell adhesion and TNF-α-induced expression of vascular adhesion molecule 1 （VCAM-1） and E-selectin in the cells, which was also reversed by transfection with PXR siRNA. Conclusion： Ginkgolide B exerts anti-apoptotic and anti-inflammatory effects on endothelial cells via PXR activation, suggesting that a PXR-mediated endothelial detoxiflcation program may be important for protecting endothelial cells from xeno- and endobiotic-induced injuries.