Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus.
Department of Biochemistry and Molecular Pharmacology
Adult; Animals; Cardiovascular Diseases; Female; Humans; Lipoproteins, HDL; Lupus Erythematosus, Systemic; Male; Mice; Middle Aged; NADPH Oxidase; Neutrophils; Nitric Oxide Synthase; Oxidation-Reduction; Oxidative Stress; Peroxidase
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Musculoskeletal Diseases | Therapeutics
OBJECTIVE: Oxidative stress and oxidized high-density lipoprotein (HDL) are implicated as risk factors for cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Yet, how HDL is oxidized and rendered dysfunctional in SLE remains unclear. Neutrophil extracellular traps (NETs), the levels of which are elevated in lupus, possess oxidant-generating enzymes, including myeloperoxidase (MPO), NADPH oxidase (NOX), and nitric oxide synthase (NOS). We hypothesized that NETs mediate HDL oxidation, impairing cholesterol efflux capacity (CEC).
METHODS: Plasma MPO levels and CEC activity were examined in controls and lupus patients, and 3-chlorotyrosine (MPO specific) and 3-nitrotyrosine (derived from reactive nitrogen species) were quantified in human HDL. Multivariable linear models were used to estimate and test differences between groups. HDL was exposed to NETs from control and lupus neutrophils in the presence or absence of MPO, NOX, NOS inhibitors, and chloroquine (CQ). Murine HDL oxidation was quantified after NET inhibition in vivo.
RESULTS: SLE patients displayed higher MPO levels and diminished CEC compared to controls. SLE HDL had higher 3-nitrotyrosine and 3-chlorotyrosine content than control HDL, with site-specific oxidation signatures on apolipoprotein A-I. Experiments with human and murine NETs confirmed that chlorination was mediated by MPO and NOX, and nitration by NOS and NOX. Mice with lupus treated with the NET inhibitor Cl-amidine displayed significantly decreased HDL oxidation. CQ inhibited NET formation in vitro.
CONCLUSION: Active NOS, NOX, and MPO within NETs significantly modify HDL, rendering the lipoprotein proatherogenic. Since NET formation is enhanced in SLE, these findings support a novel role for NET-derived lipoprotein oxidation in SLE-associated CVD and identify additional proatherogenic roles of neutrophils and putative protective roles of antimalarials in autoimmunity. domain in the USA.
DOI of Published Version
Arthritis Rheumatol. 2014 Sep;66(9):2532-44. doi: 10.1002/art.38703. Link to article on publisher's site
Arthritis and rheumatology (Hoboken, N.J.)
Smith CK, Vivekanandan-Giri A, Tang C, Knight JS, Mathew A, Padilla RL, Gillespie BW, Carmona-Rivera C, Liu X, Subramanian V, Hasni S, Thompson PR, Heinecke JW, Saran R, Pennathur S, Kaplan MJ. (2014). Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus.. Thompson Lab Publications. https://doi.org/10.1002/art.38703. Retrieved from https://escholarship.umassmed.edu/thompson/8