title: Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1.
abstract: Atherosclerosis is considered to be a combined disorder of lipid metabolism and chronic inflammation. Recent studies have reported that liver X receptors (LXRs) are involved in lipid metabolism and inflammation and that LXR agonists inhibit atherogenesis. In contrast, angiotensin II is well known to accelerate atherogenesis through activation of the angiotensin II type 1 receptor (AT1R). To better understand the mechanism of LXR on the prevention of atherogenesis, we examined whether activation of LXR affects AT1R expression in vascular smooth muscle cells. T0901317, a synthetic LXR ligand, decreased AT1R mRNA and protein expression with a peak reduction at 6 hours and 12 hours of incubation, respectively. A well-established ligand of LXR, 22-(R)-hydroxycholesterol, also suppressed AT1R expression. The downregulation of AT1R by T0901317 required de novo protein synthesis. AT1R gene promoter activity measured by luciferase assay revealed that the DNA segment between -61 bp and +25 bp was sufficient for downregulation. Luciferase construct with a mutation in Sp1 binding site located in this segment lost its response to T0901317. T0901317 decreased Sp1 serine phosphorylation. Although preincubation of vascular smooth muscle cells with T0901317 for 30 minutes had no effect on angiotensin II-induced extracellular signal-regulated kinase phosphorylation, phosphorylation of extracellular signal-regulated kinase by angiotensin II was markedly suppressed after 6 hours of preincubation. These results indicate that the suppression of AT1R may be one of the important mechanisms by which LXR ligands exert antiatherogenic effects.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Imayama
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.forename: Dan
authors.initials: D
authors.lastname: Patton
authors.forename: Keita
authors.initials: K
authors.lastname: Inanaga
authors.forename: Ryohei
authors.initials: R
authors.lastname: Miyazaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohtsubo
authors.forename: Qingping
authors.initials: Q
authors.lastname: Tian
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yano
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D016296:Mutagenesis; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000804:Angiotensin II; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D018160:Receptors, Cytoplasmic and Nuclear; D016329:Sp1 Transcription Factor; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides