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High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis.

ABSTRACT: Phagocyte-derived myeloperoxidase (MPO) and pro-inflammatory high density lipoprotein (HDL) associate with rheumatoid arthritis (RA), but the link between MPO and HDL has not been systematically examined. In this study, we investigated whether MPO can oxidise HDL and determined MPO-specific oxidative signature by apoA-1 by peptide mapping in RA subjects with and without known cardiovascular disease (CVD).Two MPO oxidation products, 3-chlorotyrosine and 3-nitrotyrosine, were quantified by tandem mass spectrometry (MS/MS) in in vitro model system studies and in plasma and HDL derived from healthy controls and RA subjects. MPO levels and cholesterol efflux were determined. Site-specific nitration and chlorination of apoA-1 peptides were quantified by MS/MS.RA subjects demonstrated higher levels of MPO, MPO-oxidised HDL and diminished cholesterol efflux. There was marked increase in MPO-specific 3-chlorotyrosine and 3-nitrotyrosine content in HDL in RA subjects consistent with specific targeting of HDL, with increased nitration in RA subjects with CVD. Cholesterol efflux capacity was diminished in RA subjects and correlated inversely with HDL 3-chlorotyrosine suggesting a mechanistic role for MPO. Nitrated HDL was elevated in RACVD subjects compared with RA subjects without CVD. Oxidative peptide mapping revealed site-specific unique oxidation signatures on apoA-1 for RA subjects with and without CVD.We report an increase in MPO-mediated HDL oxidation that is regiospecific in RA and accentuated in those with CVD. Decreased cholesterol efflux capacity due to MPO-mediated chlorination is a potential mechanism for atherosclerosis in RA and raises the possibility that oxidant resistant forms of HDL may attenuate this increased risk.

SUBMITTER: Vivekanandan-Giri A

PROVIDER: S-EPMC4151549 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis.

Vivekanandan-Giri Anuradha A Slocum Jessica L JL Byun Jaeman J Tang Chongren C Sands Robin L RL Gillespie Brenda W BW Heinecke Jay W JW Saran Rajiv R Kaplan Mariana J MJ Pennathur Subramaniam S

Annals of the rheumatic diseases 20130112 10

<h4>Objective</h4>Phagocyte-derived myeloperoxidase (MPO) and pro-inflammatory high density lipoprotein (HDL) associate with rheumatoid arthritis (RA), but the link between MPO and HDL has not been systematically examined. In this study, we investigated whether MPO can oxidise HDL and determined MPO-specific oxidative signature by apoA-1 by peptide mapping in RA subjects with and without known cardiovascular disease (CVD).<h4>Methods</h4>Two MPO oxidation products, 3-chlorotyrosine and 3-nitroty ...[more]

PMID: 23313808

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Project description:OBJECTIVE:Patients with rheumatoid arthritis (RA) have an increased risk of coronary heart disease (CHD). Some RA therapies may modify this risk, but the underlying mechanisms are unclear. The cholesterol efflux capacity of high-density lipoprotein (HDL) is associated with a reduced CHD risk in non-RA populations; however, inflammation may impair the function of HDL. The aim of this study was to evaluate whether reduced inflammation resulting from treatment with methotrexate (MTX), adalimumab (ADA), or tocilizumab (TCZ) would increase the net cholesterol efflux capacity of HDL in patients with RA. METHODS:A longitudinal multicenter study repository (Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository) provided clinical information for and serum samples from 70 patients with RA before and 6 months after starting treatment with a new drug (MTX [n?=?23], ADA [n?=?22], or TCZ [n?=?25]). Disease activity was measured using the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). The net cholesterol efflux capacity was measured in paired serum samples using THP-1 macrophages, and total cellular cholesterol was measured by fluorometric assay. RESULTS:The DAS28-ESR decreased with all treatments (P?<?0.001). Net cholesterol efflux capacity was not significantly changed after 6 months of new RA therapy (mean?±?SD 36.9?±?17.3% units at baseline versus 38.0%?±?16.9% units at 6 months [P?=?0.58]). However, change in net cholesterol efflux capacity was associated with change in the DAS28-ESR (??=?-0.25, P?=?0.04). In a post hoc analysis of patients with impaired net cholesterol efflux capacity at baseline, treatment with TCZ resulted in significant improvement in net cholesterol efflux capacity (21.9?±?14.7% units at baseline versus 31.3%?±?12.8% units at 6 months [P?<?0.02]), but this was not observed with MTX or ADA. CONCLUSION:Net cholesterol efflux capacity of HDL cholesterol did not change significantly after 6 months of new RA therapy, except in patients with impaired baseline cholesterol efflux capacity who were receiving TCZ. Change in disease activity was associated with change in the net cholesterol efflux capacity.

Dataset Information

High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis.

Publications

High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis.

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