title: 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.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China; Department of Physiology, Guangdong Medical College, Dongguan, People's Republic of China; and.
authors.forename: Aihui
authors.initials: A
authors.lastname: Fan
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China;
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Guangdong Medical College, Dongguan, People's Republic of China.
authors.forename: Jilun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China;
authors.forename: Lixian
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China;
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China;
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China; bing@smu.edu.cn.
authors.forename: Xuliang
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China;
authors.forename: Qiaobing
authors.initials: Q
authors.lastname: Huang
mesh_terms: D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation; D017097:Electric Impedance; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D008246:Lysophospholipids / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D034622:RNA Interference; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; D008246:Lysophospholipids; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: atherosclerosis; inflammatory gene; liver X receptor; microRNA; sphingosine 1-phosphate receptor