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.).
Circ Res. 2014 Mar 14;114(6):947-56. doi: 10.1161/CIRCRESAHA.114.303312. Epub 2014 Jan 14.
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.
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.
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.
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.
中性粒细胞胞外诱捕网（NET）的形成可促进病变动脉中的血管损伤、血栓形成和干扰素-α产生的浆细胞样树突状细胞的激活。肽基精氨酸脱亚氨酶抑制是一种可以减少体内 NET 形成的策略。
检测肽基精氨酸脱亚氨酶抑制，一种针对动脉疾病的新方法，是否可以减少动脉粥样硬化小鼠模型中的血管损伤并抑制固有免疫反应。
载脂蛋白-E（Apoe）（-/-）小鼠表现出增强的 NET 形成，对 NET 产生自身抗体，并在病变动脉中表达高水平的干扰素-α。用肽基精氨酸脱亚氨酶抑制剂 Cl-amidine 对 Apoe（-/-）小鼠进行为期 11 周的每日注射治疗。肽基精氨酸脱亚氨酶抑制可阻止 NET 形成，减少动脉粥样硬化病变面积，并延迟光化学损伤模型中的颈动脉血栓形成时间。动脉粥样硬化负担的减少伴随着向动脉募集的网织中性粒细胞和巨噬细胞减少，以及动脉中干扰素-α表达减少。
阻断 NET 形成的药物干预可减少小鼠系统中的动脉粥样硬化负担和动脉血栓形成。这些结果支持异常 NET 形成通过调节固有免疫反应在动脉粥样硬化发病机制中的作用。
