Recombinant Thrombomodulin Attenuates Preeclamptic Symptoms by Inhibiting High-Mobility Group Box 1 in Mice
Recombinant Thrombomodulin Attenuates Preeclamptic Symptoms by Inhibiting High-Mobility Group Box 1 in Mice
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DOI：
10.1210/endocr/bqaa248
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发表时间：
2021-01-06
期刊：
影响因子：
4.8
通讯作者：
Fujii, Tomoyuki
中科院分区：
文献类型：
--
作者：
Oda, Hiroko;Nagamatsu, Takeshi;Fujii, Tomoyuki
先兆子痫（PE）是一种常见的妊娠并发症，涉及全身性内皮功能障碍和炎症反应，主要是由于胎盘损伤。重组血栓调节蛋白（rTM）是一种新型抗凝剂，可通过抑制促炎介质高迁移率族蛋白1（HMGB 1）发挥独特的抗炎内皮修复作用，临床上用于治疗弥漫性血管内凝血（DIC）。在这里，我们使用小鼠模型和人滋养层细胞验证了rTM作为一种新的治疗药物对PE的疗效。我们揭示了rTM在血管紧张素II（Ang II）诱导的PE小鼠模型中的治疗潜力。注射rTM可显著减轻PE的临床特征，如高血压、蛋白尿、胎儿生长受限和胎盘血管受损。母体可溶性fms样酪氨酸激酶-1（sFlt-1）的升高（这是一种公认的导致全身性内皮功能障碍的PE的致病因素）在rTM治疗后受到抑制。支持这些发现，我们的体外实验表明，rTM减少血管紧张素II触发的sFlt-1在人类滋养层细胞的过度生产。此外，白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α），PE发病机制中众所周知的关键炎症介质，被rTM减少。SiRNA敲除实验进一步证实了这些过程是由HMGB 1直接介导的。我们的研究表明，rTM作为HMBG 1抑制剂发挥其临床作用，并改善胎盘功能障碍，这是PE发病机制的核心。我们的研究结果表明，rTM可能是一个有前途的治疗，显着改善PE患者的结果。
Preeclampsia (PE) is a common gestational complication that involves systemic endothelial dysfunction and inflammatory responses primarily due to placental damage. Recombinant thrombomodulin (rTM), a novel anticoagulant clinically used for disseminated intravascular coagulation, is reported to have a unique anti-inflammatory endothelial repair function by inhibiting proinflammatory mediator high-mobility group box 1 (HMGB1).Despite the severe patient outcomes, there are currently no effective therapeutic options to treat PE. Here, we verified the efficacy of rTM as a novel therapeutic agent for PE using a murine model and human trophoblast cells.We revealed the therapeutic potential of rTM in an angiotensin II(Ang II)-induced PE mouse model. Injection of rTM significantly attenuated clinical features of PE, such as hypertension, proteinuria, fetal growth restriction, and impaired placental vasculature. Elevation of maternal soluble fms-like tyrosine kinase-1 (sFlt-1), a well-accepted causal factor of PE that induces systemic endothelial dysfunction, was suppressed in response to rTM treatment. Supporting these findings, our in vitro experiments revealed that rTM reduces Ang II-triggered overproduction of sFlt-1 in human trophoblast cells. Moreover, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), well-known key inflammatory mediators in PE pathogenesis, were diminished by rTM. SiRNA knockdown experiments further determined that these processes were directly mediated by HMGB1.Our studies demonstrate that rTM exerts its clinical effect as HMBG1 inhibitor and ameliorates placental dysfunction, which is central to PE pathogenesis. Our findings suggest that rTM could be a promising therapeutic that significantly improve the outcomes of PE patients.