Impact of serum high mobility group box 1 and soluble receptor for advanced glycation end-products on subclinical atherosclerosis in patients with granulomatosis with polyangiitis.

Alexandre W S De Souza,Karina De Leeuw,Cees G M Kallenberg,Pieter C Limburg,Coen A Stegeman,Johanna Westra,Marc Bijl,Mirjan M Van Timmeren,Andreas Zirlik

doi:10.1371/journal.pone.0096067

Abstract

The objective of this study was to evaluate whether levels of high mobility group box 1 (HMGB1) in granulomatosis with polyangiitis (GPA) patients are associated with carotid atherosclerosis, related to levels of soluble receptor for advanced glycation end-products (sRAGE) and influenced by immunosuppressive or lipid-lowering therapy. Twenty-three GPA patients and 20 controls were evaluated for HMGB1- and sRAGE levels and for carotid atherosclerosis using ultrasound to determine intima-media thickness (IMT). In vitro the effect of atorvastatin on the production of HMGB1 by lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVEC) was assessed. Serum HMGB1 and sRAGE levels did not differ between patients and controls. A negative correlation was found between sRAGE and maximum IMT but HMGB1 and carotid IMT were not related. HMGB1 levels were reduced in GPA patients on statins and prednisolone. In vitro, atorvastatin reduced HMGB1 levels in supernatants of activated HUVEC. In conclusion, carotid IMT is inversely correlated with sRAGE levels but not with HMGB1 levels. Statins and prednisolone are associated with reduced serum HMGB1 levels and atorvastatin decreases HMGB1 release by activated HUVEC in vitro, indicating an additional anti-inflammatory effect of statins.

Highlights

High mobility group box 1 (HMGB1) is a nuclear non-histone DNA binding protein that upon cellular death or activation is released into the extracellular milieu and acts as an alarmin
We hypothesized that serum HMGB1 levels contribute to subclinical atherosclerosis in granulomatosis with polyangiitis (GPA) and that this process is influenced by Soluble receptor for advanced glycation end-products (RAGE) (sRAGE) and by treatment with prednisolone and statins
Correlation was present between HMGB1 and sRAGE, between overall mean carotid intima-media thickness (IMT) and cumulative Birmingham Vasculitis Activity Score (BVAS) or between overall mean carotid IMT and time in remission since last relapse/

Summary

Introduction

High mobility group box 1 (HMGB1) is a nuclear non-histone DNA binding protein that upon cellular death or activation is released into the extracellular milieu and acts as an alarmin. Extracellular HMGB1 stimulates cytokine production, cell proliferation, chemotaxis, angiogenesis, and cell differentiation through binding to its receptors that include the receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLR)-2, TLR4 and TLR9 [1]. Individuals with subclinical atherosclerosis and cardiovascular (CV) events present high HMGB1 levels whereas atorvastatin decreases serum HMGB1 in hyperlipidemia [5,6]. Patients with GPA present increased advanced glycation end-products (AGEs) accumulation compared to controls and this accumulation is negatively correlated with sRAGE levels [8]. We hypothesized that serum HMGB1 levels contribute to subclinical atherosclerosis in GPA and that this process is influenced by sRAGE and by treatment with prednisolone and statins

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Conclusion