Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway

Background/Aims: Angiotensin II (Ang II) regulates the expression of some core clock genes; excess Ang II leads to atherosclerosis advancement. Macrophage Rev-erb alpha mediates clockwork and inflammation, and plays a role in atherosclerotic lesion progression. However, the role of Ang II in regulating Rev-erb alpha expression in macrophages remains unclarified. Methods: We induced THP-1 macrophages by phorbol 12-myristate 13-acetate and investigated the effect of Ang II on Rev-erb alpha expression via real-time polymerase chain reaction, western blotting and small interfering RNA (siRNA) techniques. The cytotoxicity of the Rev-erb alpha agonist SR9009 was analyzed using a (3-[4,5-dimethylthiazol-2-yl])-2,5-diphenyltetrazolium bromide assay. Results: Ang II suppressed Rev-erb alpha mRNA and protein expression in THP-1 macrophages in a dose and time dependent manner. This effect was mediated via Ang II type 1 receptor (AT1R), and not Ang II type 2 receptor or peroxisome proliferator-activated receptor gamma (PPAR gamma). Consistent with Rev-erb alpha expression regulated by Ang II, the liver X receptor alpha (LXR alpha) protein expression was downregulated in a time-dependent manner after Ang II treatment. The activation or silence of LXR alpha significantly increased or decreased Rev-erb alpha expression regulated by Ang II, respectively. This suggests that LXR alpha is involved in the effect of Ang II on Rev-erb alpha expression. MMP-9 mRNA expressions were significantly suppressed by SR9009 in THP-1 and RAW264.7 macrophages; moreover, SR9009-treatment significantly reduced Ang II-induced MMP-9 protein expressions in two types of macrophages. Conclusion: Ang II downregulates Rev-erb alpha expression in THP-1 macrophages via the AT1R/LXR alpha pathway. (C) 2018 The Author(s) Published by S. Karger AG, Basel