CYP19A1, MIF and ABCA1 genes are targets of the RORα in monocyte and endothelial cells.

Abstract

ROR is a member of nuclear receptor superfamily of transcription factors, which has a vital role in the regulation of various physiological processes. Cholesterol is a known ligand of ROR and is one of the key components that take part in cardiovascular diseases such as atherosclerosis. Therefore, it is possible that ROR might have a role in the development of atherosclerosis. To test this hypothesis, we investigated the presence of novel ROR response elements (ROREs) located in the promoter of CYP19A1, MIF and ABCA1 genes. Briefly, the occupancy of ROR in the promoter regions of these genes was demonstrated in THP-1 and HUVEC cell lines by ChIP analysis. In order to modulate ROR activity, THP-1 and HUVEC cells were treated with specific ROR ligands (CPG 52608 and SR1001) and then the expression levels of target genes were analysed. In the next step, we tested whether ROR activity in THP-1 macrophages was influenced by the presence of simvastatin, a cholesterol lowering drug. We found that in the presence of simvastatin the expression of the investigated target genes were down regulated and that this regulation was partially prevented by CPG 52608 and SR1001. Results of this study suggest that CYP19A1, MIF and ABCA1 are the direct target genes of ROR. In conclusion, it is important to demonstrate that certain genes involved in the development of atherosclerosis could be modulated by an inducible transcription factor. Therefore, these results offer a potential therapeutic approach for the treatment of atherosclerosis.