Amadio Patrizia, Tarantino Eva, Sandrini Leonardo, Tremoli Elena, Barbieri Silvia S
Silvia S. Barbieri, PhD, Centro Cardiologico Monzino, IRCCS, Via Parea 4, 20138 Milano, Italy, Tel.: +39 02 50318357, Fax: +39 02 50318250, E-mail:
Thromb Haemost. 2017 Jul 26;117(8):1486-1497. doi: 10.1160/TH16-12-0968. Epub 2017 May 24.
Deep-vein thrombosis (DVT) is a common condition that often leads to pulmonary thromboembolism (VTE) and death. The role of prostaglandin-endoperoxide synthase (PTGS)2 in arterial thrombosis has been well established, whereas its impact in venous thrombosis remains unclear. Here, we showed that PTGS2 deletion predisposes to venous thrombosis as suggested by greater clot firmness and clot elasticity, by higher plasma levels of functional fibrinogen, factor VIII and PAI-1 activity, and proved by bigger thrombi detected after inferior vena cava ligation (IVCL) compared to WT mice. PTGS2 thrombi have greater fibrin content, higher number of F4/80, TF and ANXA2 cells, and lower S100A10 cells. Remarkably, monocyte depletion reduced thrombus size in mutant mice, suggesting an important role of PTGS2 monocytes in this experimental setting. Interestingly, PTGS2 deletion reduced membrane ANXA2, and total S100A10, promoted assembly of ANXA2/p50NF-kB complex and its nuclear accumulation, and induced TF in peritoneal macrophages, whereas ANXA2 silencing decreased dramatically TF. Finally, Carbaprostacyclin treatment prevented venous thrombus formation induced by IVCL in mutant mice, reduced the ANXA2 binding to p50NF-kB subunit and its nuclear trafficking, and decreased TF in PTGS2 macrophages. PTGS2 deletion, changing the natural distribution of ANXA2 in monocytes/macrophages, increases TF expression and activity predisposing to venous thrombosis. Interestingly, Carbaprostacyclin treatment, inhibiting nuclear ANXA2 trafficking, controls monocyte TF activity and prevents DVT occurrence. Our data are of help in elucidating the mechanisms by which PTGS2 inhibition increases DVT risk, and suggest a new role for ANXA2 in venous thrombosis.
深静脉血栓形成（DVT）是一种常见病症，常导致肺血栓栓塞（VTE）和死亡。前列腺素 - 内过氧化物合酶（PTGS）2在动脉血栓形成中的作用已得到充分证实，而其在静脉血栓形成中的影响仍不清楚。在此，我们表明，PTGS2缺失易导致静脉血栓形成，这表现为血凝块硬度和弹性增加、功能性纤维蛋白原、凝血因子VIII和纤溶酶原激活物抑制剂 - 1（PAI - 1）活性的血浆水平升高，并且与野生型小鼠相比，下腔静脉结扎（IVCL）后检测到的血栓更大，从而证明了这一点。PTGS2血栓具有更高的纤维蛋白含量、更多的F4/80、组织因子（TF）和膜联蛋白A2（ANXA2）细胞，以及更少的S100A10细胞。值得注意的是，单核细胞耗竭减少了突变小鼠的血栓大小，表明在该实验环境中PTGS2单核细胞具有重要作用。有趣的是，PTGS2缺失减少了膜ANXA2和总S100A10，促进了ANXA2/p50核因子 - κB（NF - κB）复合物的组装及其核内积累，并诱导腹膜巨噬细胞中的TF，而ANXA2沉默则显著降低TF。最后，卡前列环素治疗可预防突变小鼠中IVCL诱导的静脉血栓形成，减少ANXA2与p50NF - κB亚基的结合及其核转运，并降低PTGS2巨噬细胞中的TF。PTGS2缺失改变了ANXA2在单核细胞/巨噬细胞中的天然分布，增加了TF表达和活性，易导致静脉血栓形成。有趣的是，卡前列环素治疗通过抑制核ANXA2转运，控制单核细胞TF活性并预防DVT的发生。我们的数据有助于阐明PTGS2抑制增加DVT风险的机制，并提示ANXA2在静脉血栓形成中的新作用。
