Oxidized low-density lipoprotein suppresses expression of prostaglandin E receptor subtype EP3 in human THP-1 macrophages

Xuxia Sui; Yanmin Liu; Qi Li; Gefei Liu; Xuhong Song; Zhongjing Su; Xiaolan Chang; Yingbi Zhou; Bin Liang; Dongyang Huang

doi:10.1371/journal.pone.0110828

Oxidized low-density lipoprotein suppresses expression of prostaglandin E receptor subtype EP3 in human THP-1 macrophages

PLoS One. 2014 Oct 21;9(10):e110828. doi: 10.1371/journal.pone.0110828. eCollection 2014.

Authors

Affiliations

¹ Department of Cell Biology, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, Guangdong, China.
² Department of Cardiovascular Research Center, Shantou University Medical College, Shantou, Guangdong, China.

Abstract

EP3, one of four prostaglandin E2 (PGE2) receptors, is significantly lower in atherosclerotic plaques than in normal arteries and is localized predominantly in macrophages of the plaque shoulder region. However, mechanisms behind this EP3 expression pattern are still unknown. We investigated the underlying mechanism of EP3 expression in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages with oxidized low-density lipoprotein (oxLDL) treatment. We found that oxLDL decreased EP3 expression, in a dose-dependent manner, at both the mRNA and protein levels. Moreover, oxLDL inhibited nuclear factor-κB (NF-κB)-dependent transcription of the EP3 gene by the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Finally, chromatin immunoprecipitation revealed decreased binding of NF-κB to the EP3 promoter with oxLDL and PPAR-γ agonist treatment. Our results show that oxLDL suppresses EP3 expression by activation of PPAR-γ and subsequent inhibition of NF-κB in macrophages. These results suggest that down-regulation of EP3 expression by oxLDL is associated with impairment of EP3-mediated anti-inflammatory effects, and that EP3 receptor activity may exert a beneficial effect on atherosclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / drug effects*
Cell Line
Gene Expression Regulation / drug effects
Humans
Lipoproteins, LDL / administration & dosage*
Lipoproteins, LDL / metabolism
Macrophages / drug effects
Macrophages / metabolism
NF-kappa B / biosynthesis
PPAR gamma / biosynthesis*
PPAR gamma / genetics
Plaque, Atherosclerotic / metabolism
Plaque, Atherosclerotic / pathology
RNA, Messenger / biosynthesis
Receptors, Prostaglandin E, EP3 Subtype / biosynthesis*
Receptors, Prostaglandin E, EP3 Subtype / genetics
Tetradecanoylphorbol Acetate / administration & dosage
Tetradecanoylphorbol Acetate / analogs & derivatives

Substances

Lipoproteins, LDL
NF-kappa B
PPAR gamma
PTGER3 protein, human
RNA, Messenger
Receptors, Prostaglandin E, EP3 Subtype
oxidized low density lipoprotein
4-O-methyl-12-O-tetradecanoylphorbol 13-acetate
Tetradecanoylphorbol Acetate

Grants and funding

National Basic Research Project of China (program 973, grant number 2010CD912503), the National Natural Science Foundation of China (grant numbers 31371333 and 31071153), and Guangdong Natural Science Foundation of China (grant number S2012030006289). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.