Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model.

Cuiqing Liu,Zhekang Ying,Liubov Gushchina,Xiaohua Xu,Aixia Wang,Jixin Zhong,Thomas Kampfrath,Xiaoquan Rao,Sanjay Rajagopalan,Andrei Maiseyeu,Rajagopal Desikan,Sampath Parthasarathy,Qinghua Sun,Jeffrey Deiuliis

doi:10.1371/journal.pone.0050767

Cuiqing Liu, Zhekang Ying + Show 12 more

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https://doi.org/10.1371/journal.pone.0050767

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Abstract

Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis. However, the effect of synthetic myeloperoxidase inhibitors on atherosclerosis has been insufficiently studied. In this study, ApoE−/− mice were randomized to low- and high-dose INV-315 groups for 16 weeks on high-fat diet. INV-315 resulted in reduced plaque burden and improved endothelial function in response to acetylcholine. These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a decrease in iNOS gene expression, superoxide production and nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b+/Ly6Glow/7/4hi monocytes were significantly decreased in response to INV-315 treatment. Acute pretreatment with INV-315 blocked TNFα-mediated leukocyte adhesion in cremasteric venules and inhibited myeloperoxidase activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Our results suggest that myeloperoxidase inhibition may exert anti-atherosclerotic effects via inhibition of oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of myeloperoxidase in atherosclerosis.

Highlights

Myeloperoxidase (MPO) is a hemoprotein produced by polymorphonuclear neutrophils and macrophages and is thought to play a role in atherosclerosis through its role in inflammation and oxidative modification of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) [1,2,3]
Circulating cytokine levels were determined by Cytometric Bead Array (BD Biosciences, San Diego, CA). 50 ml Plasma was incubated with beads specific for interferon c (IFN-c), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and IL-10 according to the manufacturer’s instructions
Effects of MPO inhibition on metabolic parameters There were no differences in body weight between the groups at baseline. 16-week of high-fat diet (HFD) feeding resulted in significant increase in body weight without significant effects between control and INV-315-treated groups at the end of the treatment period (Table S7)

Summary

Introduction

Myeloperoxidase (MPO) is a hemoprotein produced by polymorphonuclear neutrophils and macrophages and is thought to play a role in atherosclerosis through its role in inflammation and oxidative modification of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) [1,2,3]. MPO is present in human atherosclerotic areas rich in macrophages and consistent with its role, mass spectrometric approaches reveal lipid and protein oxidation products characteristic of its peroxidase function [2,6]. MPO-dependent nitration of amino acid residues such as tyrosine has been linked to altered protein structure and function of lipoproteins. MPO-modified HDL impairs its ability to partake in reverse cholesterol transport (RCT) [7,8]. These observations provide strong evidence that MPO is present and enzymatically active in atherosclerotic tissue

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