Liver X receptor-α and miR-130a-3p regulate expression of sphingosine 1-phosphate receptor 2 in human umbilical vein endothelial cells

Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signaling. Sphingosine 1-phosphate receptor 2 (S1PR2), an important inflammatory gene product, plays a role in the development of various inflammatory diseases. It was proposed that S1PR2 might be regulated by LXR-alpha. In the present study, the effect of LXR-alpha on tumor necrosis factor-alpha (TNF-alpha)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-alpha led to an increase in S1PR2 expression and triggered a downregulation of LXR-alpha expression in HUVECs as well. Downregulation of LXR-alpha with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-alpha-induced expression of S1PR2 in HUVECs. Activation of LXR-alpha by agonist GW3965 inhibited both primary and TNF-alpha -induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-alpha induced a significant decrease in miR-130a-3p expression. Overexpression of miR-130a-3p with mimic product reduced S1PR2 protein expression, and inhibition of miR-130a-3p by specific inhibitor resulted in an increase in S1PR2 protein expression. Furthermore, activation of LXRs with agonist enhanced the expression of miR-130a-3p, and knockdown of LXR-alpha by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-alpha might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-alpha attenuates the activity of LXR-alpha and results in enhanced S1PR2 expression.