Inhibition of liver x receptor/retinoid X receptor-mediated transcription contributes to the proatherogenic effects of arsenic in macrophages in vitro.
Arterioscler Thromb Vasc Biol
; 30(6): 1228-36, 2010 Jun.
Article
en En
| MEDLINE
| ID: mdl-20339114
OBJECTIVE: To determine whether arsenic inhibits transcriptional activation of the liver X receptor (LXR)/retinoid X receptor (RXR) heterodimers, thereby impairing cholesterol efflux from macrophages and potentially contributing to a proatherogenic phenotype. METHODS AND RESULTS: Arsenic is an important environmental contaminant and has been linked to an increased incidence of atherosclerosis. Previous findings showed that arsenic inhibits transcriptional activation of type 2 nuclear receptors, known to heterodimerize with RXR. Environmentally relevant arsenic doses decrease the LXR/RXR ligand-induced expression of the LXR target genes (ABCA1 and SREBP-1c). Arsenic failed to decrease cAMP-induced ABCA1 expression, suggesting a selective LXR/RXR effect. This selectivity correlated with the ability of arsenic to decrease LXR/RXR ligand-induced, but not cAMP-induced, cholesterol efflux. By using chromatin immunoprecipitation assays, we found that arsenic inhibits the ability of LXR/RXR ligands to induce activation markers on the ABCA1 and SREBP-1c promoters and blocks ligand-induced release of the nuclear receptor coexpressor (NCoR) from the promoter. Arsenic did not alter the ability of LXR to transrepress inflammatory gene transcription, further supporting our hypothesis that RXR is the target for arsenic inhibition. CONCLUSIONS: Exposure to arsenic enhances the risk of atherosclerosis. We present data that arsenic inhibits the transcriptional activity of the liver X receptor, resulting in decreased cholesterol-induced gene expression and efflux from macrophages. Therefore, arsenic may promote an athersclerotic environment by decreasing the ability of macrophages to efflux excess cholesterol, thereby favoring increased plaque formation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Óxidos
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Activación Transcripcional
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Colesterol
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Receptor alfa X Retinoide
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Receptor beta X Retinoide
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Aterosclerosis
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Receptores Nucleares Huérfanos
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Macrófagos
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Canadá
Pais de publicación:
Estados Unidos