title: Activation of liver X receptor attenuates endothelin-1 expression in vascular endothelial cells.
abstract: Endothelin-1 (ET-1), predominantly produced by vascular endothelial cells (VECs), plays an important role in the pathogenesis of inflammatory diseases. Liver X receptor (LXR), a typical nuclear receptor, is known for inhibiting expression of inflammatory molecules. However, it remains unclear whether LXR suppresses ET-1 expression. In the present study, we showed that pretreatment with GW3965, a specific ligand of LXR, significantly attenuated lipopolysaccharide (LPS)-induced ET-1 in mice plasma. The in vitro experiments showed that both LXRα and β were expressed in human VECs, and they are functional as demonstrated by induction of the target gene ABCA1 after treatment with GW3965. Moreover, activation of LXR with GW3965 in human VECs dramatically attenuated the basal and LPS-stimulated ET-1 production at both transcriptional and translational levels. Luciferase reporter assays indicated that LXR activation suppressed the transcriptional activity of the human ET-1 gene promoter, and repressed the activity of a heterologous promoter driven by the response elements of activator-1 (AP-1) or nuclear factor-κB (NF-κB). Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that activation of LXR reduced the binding of the transcriptional factors AP-1 and NF-κB to the ET-1 gene promoter region. In conclusion, activation of LXR represses ET-1 expression in vivo and in vitro, which may be involved in the negatively interfering with AP-1/NF-κB signaling. These results suggest that LXRs may serve as a novel molecular target for modulating ET-1 expression in VECs, and even for the treatment of ET-1-associated inflammatory diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Yijun
authors.initials: Y
authors.lastname: Zeng
authors.forename: Yaqun
authors.initials: Y
authors.lastname: Guan
authors.forename: Zhangxue
authors.initials: Z
authors.lastname: Hu
authors.forename: Dan
authors.initials: D
authors.lastname: Zhong
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shen
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Minfang
authors.initials: M
authors.lastname: Zhang
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zheng
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
mesh_terms: D000818:Animals; D001483:Base Sequence; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D016384:Consensus Sequence; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D001565:Benzoates; D001596:Benzylamines; D019332:Endothelin-1; C473027:GW 3965; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018808:Transcription Factor AP-1