Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.
Department of Biochemistry and Molecular Pharmacology
Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; and control; Autoantibodies; Citrulline; Dendritic Cells; Drug Evaluation, Preclinical; Enzyme Inhibitors; Extracellular Space; Histones; Hydrolases; Immunity, Innate; Interferon-alpha; L-Selectin; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutropenia; Neutrophils; Ornithine; Photochemical Processes; Protein Processing, Post-Translational; Receptor, Interferon alpha-beta; Sinus of Valsalva; Tunica Intima
Biochemistry | Cardiovascular Diseases | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
RATIONALE: Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-alpha-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-alpha 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-alpha 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.
DOI of Published Version
Circ Res. 2014 Mar 14;114(6):947-56. doi: 10.1161/CIRCRESAHA.114.303312. Epub 2014 Jan 14. Link to article on publisher's site
Knight JS, Luo W, O'Dell AA, Yalavarthi S, Zhao W, Subramanian V, Guo C, Grenn RC, Thompson PR, Eitzman DT, Kaplan MJ. (2014). Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.. Thompson Lab Publications. https://doi.org/10.1161/CIRCRESAHA.114.303312. Retrieved from https://escholarship.umassmed.edu/thompson/18