title: Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Jason S
authors.initials: JS
authors.lastname: Knight
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Alexander A
authors.initials: AA
authors.lastname: O'Dell
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Yalavarthi
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Subramanian
authors.forename: Chiao
authors.initials: C
authors.lastname: Guo
authors.forename: Robert C
authors.initials: RC
authors.lastname: Grenn
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Eitzman
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D002956:Citrulline / Q000032:analysis; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005110:Extracellular Space; D006657:Histones / Q000378:metabolism; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D007113:Immunity, Innate / Q000187:drug effects*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D019041:L-Selectin / Q000032:analysis; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009503:Neutropenia / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D055668:Photochemical Processes; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000080002:Protein-Arginine Deiminase Type 4; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency; D012850:Sinus of Valsalva / Q000473:pathology; D017539:Tunica Intima / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D001323:Autoantibodies; D004791:Enzyme Inhibitors; D006657:Histones; D016898:Interferon-alpha; D008055:Lipids; C558727:N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide; D019041:L-Selectin; D053633:Receptor, Interferon alpha-beta; D002956:Citrulline; D009952:Ornithine; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse
keywords: atherosclerosis; immunology; interferon-α; neutrophils; protein-arginine deiminase; thrombosis