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

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.

• Authors: Jason S Knight, Wei Luo, Alexander A O'Dell, Srilakshmi Yalavarthi, Wenpu Zhao, Venkataraman Subramanian, Chiao Guo, Robert C Grenn, Paul R Thompson, Daniel T Eitzman, Mariana J Kaplan
• Journal: Circulation research (Circ Res) Vol. 114 Issue 6 Pg. 947-56 (Mar 14 2014) ISSN: 1524-4571 [Electronic] United States
• PMID: 24425713 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apolipoproteins E
• Autoantibodies
• Enzyme Inhibitors
• Histones
• Interferon-alpha
• Lipids
• N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
• L-Selectin
• Receptor, Interferon alpha-beta
• Citrulline
• Ornithine
• Hydrolases
• Protein-Arginine Deiminase Type 4
• peptidylarginine deiminase 4, mouse

Topics

• Animals
• Aortic Diseases (drug therapy, etiology, pathology, prevention & control)
• Apolipoproteins E (deficiency)
• Atherosclerosis (drug therapy, enzymology, etiology, immunology, pathology, prevention & control)
• Autoantibodies (biosynthesis, immunology)
• Citrulline (analysis)
• Dendritic Cells (drug effects, metabolism)
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Extracellular Space
• Histones (metabolism)
• Hydrolases (antagonists & inhibitors, physiology)
• Immunity, Innate (drug effects)
• Interferon-alpha (biosynthesis, genetics)
• L-Selectin (analysis)
• Lipids (blood)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutropenia (immunology)
• Neutrophils (drug effects, immunology, ultrastructure)
• Ornithine (analogs & derivatives, pharmacology, therapeutic use)
• Photochemical Processes
• Protein Processing, Post-Translational (drug effects)
• Protein-Arginine Deiminase Type 4
• Receptor, Interferon alpha-beta (deficiency)
• Sinus of Valsalva (pathology)
• Tunica Intima (pathology)