Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4

Sarah L Ullevig,Hong Seok Kim,Huynh Nga Nguyen,William S Hambright,Andrew J Robles,Sina Tavakoli,Reto Asmis

doi:10.1016/j.redox.2014.01.003

Abstract

AimsDietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and resultsMetabolic stress sensitizes or “primes” human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein-S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. ConclusionUA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.

Highlights

We recently reported that metabolic stress transforms monocytes into a proatherogenic phenotype, resulting in their hyper-responsiveness to chemoattractants, a process we coined monocyte priming [22]
We reported that THP-1 monocytes exposed to metabolic stress, i.e. high glucose (HG, 25 mM) plus human low-density lipoprotein (LDL) (100 mg/ml), shows a similar hypersensitivity to monocyte chemoattractant protein1 (MCP-1) as oxidatively stressed THP-1 monocytes [22]
We tested if Ursolic acid (UA) protected THP-1 monocytes against chemokine hypersensitivity and dysfunction induced by metabolic stress

Summary

Introduction

N Corresponding author at: Clinical Laboratory Sciences, School of Health Professions, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 6246, San Antonio, TX 78229-3900, United States. Studied for its anti-cancer properties, UA induces apoptosis in cancer cells and reduces tumor growth [1]. UA0s anti-inflammatory properties have been studied in the context of metabolic disorders and UA is emerging as a potential preventative and therapeutic agent for metabolic diseases.

Methods

Results

Conclusion