Session Type: Abstract Submissions (ACR)
Background/Purpose: Cardiovascular risk is significantly increased in systemic lupus erythematosus (SLE) patients. This phenomenon cannot be explained by the Framingham risk equation. Previous reports suggest that high density lipoprotein (HDL) becomes oxidized in autoimmune diseases such as rheumatoid arthritis and SLE. We previously demonstrated that phagocyte-derived myeloperoxidase (MPO) oxidizes HDL and renders the lipoprotein atherogenic by impairing reverse cholesterol transport. Neutrophil extracellular traps (NETs) are an innate antimicrobial mechanism wherein granulocytes extrude their chromatin and antimicrobial peptides, including MPO. Nitric oxide synthase (NOS) is also capable of generating the reactive nitrogen species required for HDL oxidation and is highly present in neutrophils. As a subset of lupus granulocytes termed low density granulocytes (LDGs) display an enhanced capacity to form NETs, we hypothesized that the MPO and NOS present in these structures may represent sources of HDL oxidation, thereby leading to vascular damage and acceleration of atherogenesis.
Methods: Two oxidation products, 3-chlorotyrosine and 3-nitrotyrosine were quantified by tandem mass-spectrometry (MS/MS) in plasma and HDL derived from healthy controls and lupus subjects. Site-specific nitration and chlorination of apoA-1 peptides were also quantified by MS/MS. Plasma MPO levels were determined. Isolated NETs from control neutrophils and LDGs were incubated with control, unoxidized HDL in the absence or presence of MPO- and/or NOS-specific inhibitors. The resulting levels of HDL oxidation were then quantified by MS/MS.
Results: Lupus subjects demonstrated higher levels of MPO, and altered HDL function. There was marked increase in 3-nitrotyrosine and MPO-specific 3-chlorotyrosine content in HDL from SLE subjects. Oxidative peptide mapping revealed site-specific unique oxidation signatures on apoA1 in lupus patients. NETs were significant inducers of HDL oxidation, and this phenomenon was enhanced in NETs isolated from LDGs compared to control neutrophils. HDL oxidation by NETs was blocked with incubation of NOS- and/or MPO-specific inhibitors in vitro.
Conclusion: Accelerated NET formation by LDGs leads to enhanced HDL oxidation and renders the lipoprotein proatherogenic. These observations further support the concept that aberrant NET formation in lupus leads to damage of the endothelium and promotes atherosclerosis.
C. K. Smith,
J. S. Knight,
P. R. Thompson,
M. J. Kaplan,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lupus-neutrophil-extracellular-traps-render-high-density-lipoprotein-oxidized-and-proatherogenic/