Regulation of Transcription Factor Nrf2 in Endothelial Cells by Shear Stress
|關鍵字:||內皮細胞;剪力;轉錄因子;shear stress;Nrf2;endothelial cells||公開日期:||2004||摘要:||
Nrf2 is a nuclear factor that can initiate transcription of many antioxidant response element (ARE)-mediated genes including heme oxygenase-1 (HO-1). Nrf2 has been previously found to undergo nuclear translocation in response to shear stress, in which phosphatidylinositol 3-kinase (PI3K) is involved in this process. In this study, it was found that shear stress induced translocation of cytoplasmic Nrf2 into nucleus and increased Nrf2 and HO-1 protein expression in human umbilical vein endothelial cells (HUVECs). The mRNA level of Nrf2 was found to increase in short duration. Moreover, pretreatment of HUVECs with protein synthesis inhibitors cyclohexamide (CHX) abolished Nrf2 protein expression induced by shear stress. However, pretreatment of HUVECs with PKC inhibitor calphostin C and ERK1/2 inhibitor PD98059 had no effect on nuclear translocation of Nrf2 induced by shear stress. We speculate that shear stress increases Nrf2 protein expression in HUVECs by a transcriptional mechanism that also enhances Nrf2-mediated transcriptional activation of many ARE-mediated genes. In contrast, treatment with the proteasome inhibitor (MG132) caused an accumulation of Nrf2 in nucleus and cells. This study also found that reactive oxygen species (ROS) induced the translocation of Nrf2 into nucleus and increased HO-1 protein expression. In addition, treatment with phenolic antioxidant tert-butylhydroquinone (tBHQ) induced remarkably HO-1 protein expression as well as increased the level of Nrf2 in HUVECs. Treatment of HUVECs with CHX resulted in the loss of Nrf2 within 4 h. This effect was reversed by tBHQ, indicating that tBHQ could increase Nrf2 protein stability and prevent it from proteasomal degradation. Taken together, these data suggested that Nrf2 can be regulated and activated by different mechanisms under various stimulations, which include shear stress, ROS, and tBHQ. These regulatory mechanisms include the alteration in nuclear translocation, gene expression and protein stability of Nrf2 and it’s release from Keap1. The activation of Nrf2 may result in the expression of atheroprotective HO-1 protein.
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