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

JS Knight, W Luo, AA O'Dell, S Yalavarthi… - Circulation …, 2014 - Am Heart Assoc
JS Knight, W Luo, AA O'Dell, S Yalavarthi, W Zhao, V Subramanian, C Guo, RC Grenn…
Circulation research, 2014Am Heart Assoc
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 …
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.
Am Heart Assoc