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, Jason S.; Luo, Wei; O'Dell, Alexander A.; Yalavarthi, Srilakshmi; Zhao, Wenpu; Subramanian, Venkataraman; Guo, Chiao; Grenn, Robert C.; Thompson, Paul R.; Eitzman, Daniel T.; and Kaplan, Mariana J., "Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis." (2014). Thompson Lab Publications. 18.