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

Abstract

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-α. In the present study, the effect of LXR-α on tumor necrosis factor-α (TNF-α)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-α led to an increase in S1PR2 expression and triggered a downregulation of LXR-α expression in HUVECs as well. Downregulation of LXR-α with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-α-induced expression of S1PR2 in HUVECs. Activation of LXR-α by agonist GW3965 inhibited both primary and TNF-α-induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-α 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-α by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-α might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-α attenuates the activity of LXR-α and results in enhanced S1PR2 expression.

• Authors: Aihui Fan, Qian Wang, Yongjun Yuan, Jilun Cheng, Lixian Chen, Xiaohua Guo, Qiang Li, Bo Chen, Xuliang Huang, Qiaobing Huang
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 310 Issue 3 Pg. C216-26 (Feb 01 2016) ISSN: 1522-1563 [Electronic] United States
• PMID: 26669941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Benzoates
• Benzylamines
• GW 3965
• Liver X Receptors
• Lysophospholipids
• MIRN130 microRNA, human
• MicroRNAs
• NR1H3 protein, human
• Orphan Nuclear Receptors
• Receptors, Lysosphingolipid
• S1PR2 protein, human
• Sphingosine-1-Phosphate Receptors
• TJP1 protein, human
• Tumor Necrosis Factor-alpha
• Zonula Occludens-1 Protein
• sphingosine 1-phosphate
• Sphingosine

Topics

• Benzoates (pharmacology)
• Benzylamines (pharmacology)
• Cells, Cultured
• Down-Regulation
• Electric Impedance
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Liver X Receptors
• Lysophospholipids (pharmacology)
• MicroRNAs (genetics, metabolism)
• Orphan Nuclear Receptors (agonists, genetics, metabolism)
• Permeability
• RNA Interference
• Receptors, Lysosphingolipid (agonists, genetics, metabolism)
• Signal Transduction
• Sphingosine (analogs & derivatives, pharmacology)
• Sphingosine-1-Phosphate Receptors
• Tight Junctions (drug effects, metabolism)
• Time Factors
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation
• Zonula Occludens-1 Protein (metabolism)