Uric Acid Induces Endothelial Dysfunction by Activating the HMGB1/RAGE Signaling Pathway.

Wei Cai,Ze-Lin Liu,Shan Jiang,Xi-Mei Duan,Ji-Xiong Xu,Jiao Yu,Yun-Liang Tang,Jian-Ying Liu,Chun-Ping Zhang,Ying Liu

doi:10.1155/2017/4391920

Abstract

Uric acid (UA) is a risk factor for endothelial dysfunction, a process in which inflammation may play an important role. UA increases high mobility group box chromosomal protein 1 (HMGB1) expression and extracellular release in endothelial cells. HMGB1 is an inflammatory cytokine that interacts with the receptor for advanced glycation end products (RAGE), inducing an oxidative stress and inflammatory response, which leads to endothelial dysfunction. In this study, human umbilical vein endothelial cells (HUVECs) were incubated with a high concentration of UA (20 mg/dL) after which endothelial function and the expression of HMGB1, RAGE, nuclear factor kappa B (NF-κB), inflammatory cytokines, and adhesion molecules were evaluated. UA inhibited endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production in HUVECs, increased intracellular HMGB1 expression and extracellular HMGB1 secretion, and upregulated RAGE expression. UA also activated NF-κB and increased the level of inflammatory cytokines. Blocking RAGE significantly suppressed the upregulation of RAGE and HMGB1 and prevented the increase in DNA binding activity of NF-κB and the levels of inflammatory cytokines. It also blocked the decrease in eNOS expression and NO production induced by UA. Our results suggest that high concentrations of UA cause endothelial dysfunction via the HMGB1/RAGE signaling pathway.

Highlights

Uric acid (UA), a final breakdown product of purine metabolism, is degraded by urate oxidase to allantoin and freely excreted in the urine in most mammals [1]
When human umbilical vein endothelial cells (HUVECs) were stimulated with UA for 24 h, the amount of nitric oxide (NO) release was significantly reduced versus control cells (P < 0.05) (Figure 1(a)), as was the expression of endothelial nitric oxide synthase (eNOS) protein (P < 0.05) (Figure 1(b))
These results show that a high concentration of UA can reduce the expression level of eNOS and the amount of NO released by HUVECs, which leads to endothelial dysfunction

Summary

Introduction

Uric acid (UA), a final breakdown product of purine metabolism, is degraded by urate oxidase to allantoin and freely excreted in the urine in most mammals [1]. The gene for urease in humans is a nonfunctioning pseudogene, and overproduction or decreased excretion of UA results in uniquely high level of serum UA and sometimes hyperuricemia [2,3,4]. An elevated serum level of UA in humans is associated with systemic inflammation [8], endothelial dysfunction [9], hypertension [10], and cardiovascular disease [11]. Many studies have demonstrated that hyperuricemia is an independent risk factor for cardiovascular disease [12, 13]. It is well known that hyperuricemia is one of the main risk factors for endothelial dysfunction [14, 15], in which oxidative stress and inflammation may play an important role [16,17,18]

Methods

Results

Conclusion