alpha-Zearalanol attenuates oxLDL-induced ET-1 gene expression, ET-1 secretion and redox-sensitive intracellular signaling activation in human umbilical vein endothelial cells.

alpha-Zearalanol (alpha-ZAL), a phytochemical with both antioxidant and estrogen-like properties, has been shown to retard progression of atherosclerosis and regulate cardiovascular function in part through suppression of endothelin-1 (ET-1) secretion. However, the precise nature behind alpha-ZAL-elicited inhibition on ET-1 cascade is not largely known. Oxidized low density lipoprotein (oxLDL) plays a critical role in the expression and secretion of ET-1 as well as the onset and progression of atherosclerosis through accumulation of reactive oxygen species (ROS) and activation of mitogen-activated protein kinase stress signaling cascade. Therefore, this study was designed to examine the effect of alpha-ZAL on oxLDL-induced extracellular signal-regulated kinase (ERK) phosphorylation, ROS generation, activation of the transcriptional factor activator protein-1 (AP-1), expression, secretion and promoter activity of ET-1 in human umbilical vein endothelial cells (HUVEC). ROS generation was monitored using 2,7-dichlorofluorescin fluorescence. ET-1 expression and promoter activity were evaluated by RT-PCR and luciferase assays, respectively. oxLDL (35 microg/ml) significantly enhanced ERK phosphorylation, ROS generation, AP-1 activity, mRNA expression, secretion and promoter activity of ET-1 in HUVECs, all of which were abrogated by alpha-ZAL and the antioxidant N-acetyl-l-cysteine. Collectively, these data favor the notion that alpha-ZAL antagonizes oxLDL-induced upregulation of ET-1 gene expression and secretion via suppression of oxLDL-induced ROS accumulation, ERK phosphorylation, and activation of the endothelial transcriptional factor AP-1.