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Circ Res. 2014 Mar 14;114(6):947-56. doi: 10.1161/CIRCRESAHA.114.303312. Epub 2014 Jan 14.

Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.

Author information

1
From the Department of Rheumatology (J.S.K., A.A.O., S.Y., R.C.G.) and Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI (W.L., C.G., D.T.E.); Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD (W.Z., M.J.K.); and Department of Chemistry, The Scripps Research Institute, Jupiter, FL (V.S., P.R.T.).

Abstract

RATIONALE:

Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation.

OBJECTIVE:

To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis.

METHODS AND RESULTS:

Apolipoprotein-E (Apoe)(-/-) mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe(-/-) mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression.

CONCLUSIONS:

Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses.

KEYWORDS:

atherosclerosis; immunology; interferon-α; neutrophils; protein-arginine deiminase; thrombosis

PMID:
24425713
PMCID:
PMC4185401
DOI:
10.1161/CIRCRESAHA.114.303312
[Indexed for MEDLINE]
Free PMC Article

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