DPP-4 Inhibitor Linagliptin Ameliorates Oxidized LDL-Induced THP-1 Macrophage Foam Cell Formation and Inflammation

Abstract

Introduction

Atherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects.

Methods

THP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining.

Results

The presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1.

Conclusion

Linagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.

Keywords:

• atherosclerosis
• foam cells
• Linagliptin
• CD36
• LOX-1
• ABCG-1
• ATP binding cassette transporter G1

Highlights

• Macrophage cholesterol homeostasis plays a key role in foam cell formation;

• Linagliptin ameliorates ox-LDL-induced impaired lipid accumulation and cholesterol efflux in macrophage foam cells;

• Linagliptin suppresses ox-LDL-induced production of IL-1β, IL-6, and cellular ROS;

• Linagliptin decreases ox-LDL receptor CD36 and LOX-1 expression but selectively increases the cholesterol transporter AGCG1.

Ethics Statement

Human monocytic cell line THP-1, was purchased from the American Type Culture Collection (ATCC, Rockville, USA). Experiments were approved by the ethics committee of the Ninth People’s Hospital of Chongqing.

Disclosure

The authors report no conflicts of interest for this work.