Oslo University Hospital and University of Oslo, Olso, Norway.
Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany; Lund University, Faculty of Medicine, Department of Clinical Sciences, Division of Infection Medicine, Lund, Sweden.
Thromb Res. 2018 Jan;161:36-42. doi: 10.1016/j.thromres.2017.11.012. Epub 2017 Nov 21.
The circulating zymogen form of Factor VII activating protease (FSAP) can be activated by histones and nucleosomes in vivo. These cell-death-associated nuclear factors are also actively extruded into the extracellular space by neutrophils through a process called neutrophil extracellular trap (NET) formation (NETosis). NETs are thought to be involved in host defense, inflammation as well as thrombosis. We have investigated the bidirectional interactions of FSAP and NETs. Phorbol ester-mediated NET formation was marginally stimulated by FSAP. Plasma-derived FSAP as well as exogenous FSAP bound to NETs. There was co-localization of FSAP and NETs in coronary thrombi from patients with acute myocardial infarction. Contrary to our expectations no activation of pro-FSAP by NETs was evident. However, after disintegration of NETs with DNase, a robust activation of pro-FSAP, due to release of histones from nucleosomes, was detected. The released histones were in turn degraded by FSAP. Histone cytotoxicity towards endothelial cells was neutralized by FSAP more potently than by activated protein C (APC). One more consequence of histone degradation was a decrease in nucleosome release from apoptotic neutrophils. Taken together, NETs bind to FSAP, but do not activate pro-FSAP unless histones are released from NETs by DNAse. This activation of FSAP is likely to be important in diminishing the cytotoxic effect of histones, thus limiting the damaging effect of NETosis.
循环酶原形式的因子 VII 激活蛋白酶（FSAP）可在体内被组蛋白和核小体激活。这些与细胞死亡相关的核因子也可通过中性粒细胞的一种称为中性粒细胞胞外诱捕（NET）形成（NETosis）的过程被主动挤出细胞外空间。NET 被认为参与宿主防御、炎症和血栓形成。我们研究了 FSAP 和 NET 之间的双向相互作用。佛波酯介导的 NET 形成被 FSAP 轻度刺激。血浆来源的 FSAP 以及外源性 FSAP 与 NET 结合。在急性心肌梗死患者的冠状动脉血栓中，FSAP 和 NET 存在共定位。与我们的预期相反，NET 没有明显激活前 FSAP。然而，在用 DNAse 破坏 NET 后，由于核小体中的组蛋白释放，明显检测到前 FSAP 的激活。释放的组蛋白随后被 FSAP 降解。与激活蛋白 C（APC）相比，FSAP 更有效地中和组蛋白对内皮细胞的细胞毒性。组蛋白降解的另一个后果是凋亡中性粒细胞从核小体中释放的减少。综上所述，NET 与 FSAP 结合，但不会激活前 FSAP，除非 DNAse 将组蛋白从 NET 中释放出来。这种 FSAP 的激活可能对减轻组蛋白的细胞毒性作用很重要，从而限制 NETosis 的破坏性作用。
