High-Mobility Group Box 1 From Hypoxic Trophoblasts Promotes Endothelial Microparticle Production and Thrombophilia in Preeclampsia.
High-Mobility Group Box 1 From Hypoxic Trophoblasts Promotes Endothelial Microparticle Production and Thrombophilia in Preeclampsia.
复制标题
来自缺氧滋养层的高迁移率组 Box 1 促进先兆子痫中内皮微粒的产生和血栓形成倾向。
DOI：
10.1161/atvbaha.118.310940
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发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Wu Q
中科院分区：
文献类型：
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作者：
Hu Y;Yan R;Zhang C;Zhou Z;Liu M;Wang C;Zhang H;Dong L;Zhou T;Wu Y;Dong N;Wu Q
血栓形成倾向是子痫前期 (PE) 的主要并发症，子痫前期是一种与胎盘缺氧和滋养层炎症相关的疾病。众所周知，PE 女性体内促凝血的循环微粒 (MP) 增加，但其潜在机制仍不清楚。在这项研究中，我们试图了解胎盘缺氧、循环 MP 和血栓形成倾向之间的机制。我们分析了PE女性血浆MP的蛋白质标记，发现增加的循环MP主要来自内皮细胞。在蛋白质组学研究中，我们发现高迁移率族蛋白 1 (HMGB1)（一种促炎蛋白）是缺氧滋养层刺激人脐静脉内皮细胞 (HUVEC) 产生 MP 的关键因子。免疫耗竭或抑制缺氧人滋养层条件培养基中的 HMGB1 消除了内皮 MP 刺激活性。相反，重组 HMGB1 (rHMGB1) 刺激培养的 HUVEC 中 MP 的产生。来自 rHMGB1 刺激的 HUVEC 的 MP 在体外促进血液凝固和中性粒细胞活化。怀孕小鼠注射rHMGB1可增加血浆内皮MPs并促进血液凝固。在 PE 女性中，检测到胎盘 HMGB1 表达升高，血浆 HMGB1 水平高与血浆内皮 MP 增加相关。我们的结果表明，胎盘缺氧诱导的 HMGB1 表达和滋养细胞释放是 PE 中循环内皮 MP 增加和血栓形成倾向的重要机制。在先兆子痫中，胎盘缺氧会诱导滋养层细胞表达和释放 HMGB1。高水平的血浆 HMGB1 会导致母体内皮损伤和内皮微粒产生，进而增强血液凝固和白细胞活化。
Thrombophilia is a major complication in preeclampsia (PE), a disease associated with placental hypoxia and trophoblast inflammation. PE women are known to have increased circulating microparticles (MPs) that are pro-coagulant, but the underlying mechanisms remain unclear. In this study, we sought to understand the mechanism connecting placental hypoxia, circulating MPs and thrombophilia. We analyzed protein markers on plasma MPs from PE women and found that the increased circulating MPs were mostly from endothelial cells. In proteomic studies, we identified high-mobility group box 1 (HMGB1), a pro-inflammatory protein, as a key factor from hypoxic trophoblasts in stimulating MP production in human umbilical vein endothelial cells (HUVECs). Immunodepletion or inhibition of HMGB1 in the conditioned medium from hypoxic human trophoblasts abolished the endothelial MP-stimulating activity. Conversely, recombinant HMGB1 (rHMGB1) stimulated MP production in cultured HUVECs. The MPs from rHMGB1-stimulated HUVECs promoted blood coagulation and neutrophil activation in vitro. Injection of rHMGB1 in pregnant mice increased plasma endothelial MPs and promoted blood coagulation. In PE women, elevated placental HMGB1 expression was detected and high levels of plasma HMGB1 correlated with increased plasma endothelial MPs. Our results indicate that placental hypoxia-induced HMGB1 expression and release from trophoblasts are an important mechanism underlying increased circulating endothelial MPs and thrombophilia in PE. In preeclampsia, placental hypoxia induces HMGB1 expression and release from trophoblasts. High levels of plasma HMGB1 cause maternal endothelial damage and endothelial microparticle production, which in turn enhance blood coagulation and leukocyte activation.