Nutr Res Pract.  2024 Dec;18(6):774-792. 10.4162/nrp.2024.18.6.774.

p-Coumaric acid modulates cholesterol efflux and lipid accumulation and inflammation in foam cells

• Moon HR
• Yun JM

• KMID: 2562366
• DOI: http://doi.org/10.4162/nrp.2024.18.6.774

Abstract

BACKGROUND/OBJECTIVES
Atherosclerosis is a primary cause of cardiovascular disease associated with inflammation and lipid metabolism disorders. The accumulation of cholesterol-containing macrophage foam cells characterizes the early stages. The p-coumaric acid (p-CA) contained in vegetables may have various physiological activities. The inhibitory effect of p-CA on foam cell creation in THP-1 macrophages needs clarification. In this study, we explored the impact of p-CA on foam cells by co-treatment with oxidized lowdensity lipoprotein (ox-LDL) and lipopolysaccharides (LPS), mimicking the development of atherosclerosis in vitro and studied the regulation of its underlying mechanisms.
MATERIALS/METHODS
THP-1 cells differentiated by phorbol 12-myristate 13-acetate (1 μM) for 48 h and treated in the absence or presence of p-CA for 48 h. THP-1 macrophages were treated with combined ox-LDL (20 μg/mL) and LPS (500 ng/mL) for 24 h. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assays detected cell viability. Oil red O staining allowed us to observe lipid accumulation. Western blotting and quantitative polymerase chain reactions quantified corresponding proteins and mRNA.
RESULTS
Ox-LDL and LPS for 24 h enhanced the lipid accumulation using Oil red O in treated foam cells. By contrast, p-CA treatment inhibited lipid accumulation. p-CA significantly upregulated cholesterol efflux-related genes such as ATP binding cassette transporter A1, liver-X-receptor α and peroxisome proliferator-activated receptor gamma expression. Moreover, p-CA decreased lipid accumulation-related gene such as lectin-like oxidized low-density lipoprotein receptor-1, cluster of differentiation 36 and scavenger receptor class A1 expression. Combined ox-LDL and LPS increased nuclear factor-κB (NFκB), cyclooxygenase-2 (COX-2) and pro-inflammatory (tumor necrosis factor-α [TNF-α] and interleukin [IL]-6) activation and expression compared with untreated. p-CA suppressed this increased expression of NF-κB and COX-2, TNF-α and IL-6.
CONCLUSION
p-CA may play a vital role in atherosclerosis inhibition and protective effects by suppressing lipid accumulation and foam cell creation by increasing cholesterol efflux and can be potential agents for preventing atherosclerosis.

Keyword

Atherosclerosis; foam cells; inflammation; oxidized low density lipoprotein; p-coumaric acid

Figure

• 

  Fig. 1 Effect of p-CA on cell viability of LPS-treated THP-1 cells and upregulated expression of the inflammatory factor. (A) THP-1 monocytes were exposed to 1 μM of phorbol 12-myristate 13-acetate for 48 h, pretreated with p-CA at several concentrations and then induced with or without 500 ng/mL LPS for 24 h. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Experiments were performed in triplicate, and results are presented as the mean ± SD. The protein expression levels of NF-κB and SIRT1 were determined using immunoblotting (B).LPS, lipopolysaccharides; p-CA, p-coumaric acid; NF-κB, nuclear factor-κB; SIRT1, sirtuin 1.Different letters indicate significant differences (P < 0.05) as determined by Duncan’s multiple range test.

• 

  Fig. 2 Downregulation of lipid accumulation by p-CA treatment in THP-1 foam cells. THP-1 differentiated macrophages were cultured in the absence or presence of p-CA (0–20 μM) before 24 h. Then, the THP-1 cell was cultured in LPS (500 ng/mL) containing ox-LDL (20 μg/mL) for 24 h. (A) Cells were stained with Oil Red O; microphotographs were obtained using an optical microscope, magnification 400×. (B) Stained cells were dissolved in an isopropanol solution, and the staining intensity was measured at 520 nm. Experiments were performed in triplicate, and results are presented as the mean ± SD.LPS, lipopolysaccharides; ox-LDL, oxidized low-density lipoprotein; p-CA, p-coumaric acid.Different letters indicate significant differences (P < 0.05), as determined by Duncan’s multiple range test.

• 

  Fig. 3 Inhibition of SR-A1, CD36, and LOX-1 expression by p-CA treatment in THP-1 foam cells. The protein expression levels of SR-A1, CD36, and LOX-1 were determined using (A) immunoblotting. (B, C) The relative mRNA expression levels are shown after normalization against β-actin mRNA expression. (B) CD36 and (C) LOX-1 levels. The data are expressed relative to the mRNA levels found in untreated cells, which was arbitrarily defined as 1. (D) SR-A1 levels densities were normalized to β-actin using ImageJ software. Experiments were performed at least in triplicate, and the results are presented as mean ± SD. Data were analyzed by applying the 2−ΔΔCT method.LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; SR-A1, scavenger receptor class A1; LPS, lipopolysaccharides; ox-LDL, oxidized low-density lipoprotein; p-CA, p-coumaric acid; CD36, cluster of differentiation 36.Different letters indicate significant differences (P < 0.05) as determined by Duncan’s multiple range test.

• 

  Fig. 4 Upregulation of ABCA1, LXRα, and PPARγ expression by p-CA treatment in THP-1 foam cells. The protein expression levels of ABCA1 were determined using (A) immunoblotting. Cells were harvested, and the expression of the (B) ABCA1 mRNA in ox-LDL and LPS-induced foam cells was evaluated. The protein expression levels of LXRα and PPARγ were determined using (C) immunoblotting. Cells were harvested, and the expression of the (D, E) LXRα and PPARγ mRNA in ox-LDL and LPS-induced foam cells was evaluated. (D) LXRα and (E) PPARγ levels. Data are presented as the means ± SD. Data were analyzed by applying the 2−ΔΔCT method.LPS, lipopolysaccharides; ox-LDL, oxidized low-density lipoprotein; p-CA, p-coumaric acid; ABCA1, ATP binding cassette transporter A1; LXRα, liver X receptor α; PPARγ, Peroxisome proliferator-activated receptor γ.Different letters indicate significant differences (P < 0.05) as determined by Duncan’s multiple range test.

• 

  Fig. 5 Inhibition of inflammatory cytokine secretion by p-CA treatment in co-treated with ox-LDL and LPS-induced foam cells. THP-1 foam cells were pretreated with different concentrations of p-CA (0–20 μM) for 48 h. (A, B) The secretion of IL-6 and TNF-α was measured using an enzyme-linked immunosorbent assay kit. The expression levels of TNF-α and COX-2 were measured using (C) immunoblotting. Cells were harvested, and the expression of the (D) COX-2 mRNA in ox-LDL and LPS-induced foam cells was evaluated. (E) TNF-α levels densities were normalized to β-actin using ImageJ software. Data are presented as the means ± SD.LPS, lipopolysaccharides; ox-LDL, oxidized low-density lipoprotein; p-CA, p-coumaric acid; TNF-α, tumor necrosis factor-α; IL-6, interleukin 6; COX-2, cyclooxygenase-2.Different letters indicate significant differences (P < 0.05) as determined by Duncan’s multiple range test.

• 

  Fig. 6 Inhibition of NF-κB p65 activation by p-CA treatment in co-treated with ox-LDL and LPS-induced foam cells. The levels of the NF-κB and SIRT1 proteins were measured using (A) immunoblotting. Cells were harvested, and the expression of the (B) NF-κB mRNA in ox-LDL and LPS-induced foam cells was evaluated. (C) NF-κB levels densities were normalized to β-actin using ImageJ software. Data are presented as the means ± SD. (D) THP-1 foam cells were treated with p-CA (0–20 μM) and fixed with 4% paraformaldehyde. After blocking with an appropriate buffer, cells were incubated with antibodies. Next, DAPI staining was performed to confirm the nuclei in the cells. Signals were quantified using fluorescence microscopy at 400× magnification.LPS, lipopolysaccharides; ox-LDL, oxidized low-density lipoprotein; p-CA, p-coumaric acid; NF-κB, nuclear factor-κB; SIRT1, sirtuin 1; DAPI, 4′,6-diamidino-2-phenylindole.Different letters indicate significant differences (P < 0.05) as determined by Duncan’s multiple range test.

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