High Uric Acid Activates the ROS-AMPK Pathway, Impairs CD68 Expression and Inhibits OxLDL-Induced Foam-Cell Formation in a Human Monocytic Cell Line, THP-1

Abstract

Background/Aims: Hyperuricemia is part of the metabolic-syndrome cluster of abdominal obesity, impaired glucose tolerance, insulin resistance, dyslipidemia, and hypertension. Monocytes/macrophages are critical in the development of metabolic syndrome, including gout, obesity and atherosclerosis. However, how high uric acid (HUA) exposure affects monocyte/macrophage function remains unclear. In this study, we investigated the molecular mechanism of HUA exposure in monocytes/macrophages and its impact on oxidized low-density lipoprotein (oxLDL)-induced foam-cell formation in a human monocytic cell line, THP-1. Methods: We primed THP-1 cells with phorbol-12-myristate-13-acetate (PMA) for differentiation, then exposed cells to HUA and detected the production of reactive oxygen species (ROS) and analyzed the level of phospho-AMPKα. THP-1 cells were pre-incubated with Compound C, an AMPK inhibitor, or N-acetyl-L-cysteine (NAC), a ROS scavenger, or HUA before PMA, to assess CD68 expression and phospho-AMPKα level. PMA-primed THP-1 cells were pre-treated with oxLDL before Compound C and HUA treatment. Western blot analysis was used to examine the levels of phospho-AMPKα, CD68, ABCG1, ABCA1, cyclooxygenase-2 (COX-2) and NF-κB (p65). Flow cytometry was used to assess ROS production and CD68 expression in live cells. Oil-red O staining was used to observe oxLDL uptake in cells. Results: HUA treatment increased ROS production in PMA-primed THP-1 cells; NAC blocked HUA-induced oxidative stress. HUA treatment time-dependently increased phospho-AMPKα level in PMA-primed THP-1 cells. The HUA-induced oxidative stress increased phospho-AMPKα levels, which was blocked by NAC. HUA treatment impaired CD68 expression during cell differentiation by activating the AMPK pathway, which was reversed by Compound C treatment. Finally, HUA treatment inhibited oxLDL uptake in the formation of foam cells in THP-1 cells, which was blocked by Compound C treatment. HUA treatment significantly increased the expression of ABCG1 and reversed the oxLDL-reduced ABCG1 expression but did not affect the expression of ABCA1, NF-κB (p65) or COX-2. Conclusions: HUA exposure activated the ROS-AMPK pathway, impaired CD68 expression, and inhibited oxLDL-induced foam-cell formation in a human monocytic cell line, THP-1.

U-Shaped Relationship Between Functional Outcome and Serum Uric Acid in Ischemic Stroke

“…Previous studies suggested that hyperuricemia was a risk factor for the poor outcomes [30] and through the following pathway: (1) insulin resistance [39]; (2) increasing the risk of hypertension and further aggravated atherosclerosis [40]; (3) impair the selfregulation of the arteriole [41]; (4) UA induces cardiomyocyte apoptosis through activation of calpain-1 and endoplasmic reticulum stress [42]. Furthermore, high UA exposure activated the ROS-AMPK pathway, impaired CD68 expression [43], and induced oxidative damage and inhibited the viability of cardiomyocytes by activating ERK/p38 signaling [44]. The neuroprotective function of SUA can be explained from the following aspects.…”

Zurampic Protects Pancreatic β-Cells from High Uric Acid Induced-Damage by Inhibiting URAT1 and Inactivating the ROS/AMPK/ERK Pathways

“…Oxidative stress injury has been reported to be involved in pancreatic β-cell injury induced by uric acid. It has been confirmed that uric acid can inhibit cell proliferation and increase oxidative stress, and subsequently inhibit insulin secretion by activating the reactive oxygen species (ROS)/adenosine monophosphate-activated protein kinase (AMPK)/ extracellular signal-regulated kinase (ERK) pathways [14][15][16][17][18]. Likewise, a previous study performed in pancreatic β cells has demonstrated uric acid triggers inhibition of oxidative stress and growth through activations of the AMPK and ERK signal pathways [17].…”

High Uric Acid Inhibits Cardiomyocyte Viability Through the ERK/P38 Pathway via Oxidative Stress

“…ROS are generally believed to be harmful to cells and tissues [13]. HUA levels increase oxidative stress in multiple cells [14][15][16][17][18] and cause damaged endothelia, renal injury, insulin resistance and inflammation. The three members of the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, regulate a variety of physiological processes, such as cell growth, metabolism, differentiation and cell death.…”