Cyclophilin A inhibits trophoblast migration and invasion in vitro and vivo through p38/ERK/JNK pathways and causes features of preeclampsia in mice
Cyclophilin A inhibits trophoblast migration and invasion in vitro and vivo through p38/ERK/JNK pathways and causes features of preeclampsia in mice
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亲环蛋白 A 通过 p38/ERK/JNK 通路抑制体内外滋养层迁移和侵袭，并引起小鼠先兆子痫的特征
DOI：
10.1016/j.lfs.2020.118351
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发表时间：
2020-11-15
期刊：
影响因子：
6.1
通讯作者：
Zhong, Mei
中科院分区：
文献类型：
--
作者：
Hu, Haoyue;Jiang, Jiayi;Zhong, Mei
目的：大量研究表明，母体过度炎症和绒毛外滋养细胞（EVT）侵入缺陷可能有助于先兆子痫（PE）的发展，但其潜在机制尚不清楚。一些证据表明CyPA在PE中升高。本研究旨在探讨重组人CyPA对滋养层细胞迁移和侵袭的影响，并在体内外进行实验研究。材料与方法：检测CyPA在人胎盘组织中的表达和定位，探讨CyPA对HTR 8/SVneo细胞迁移和侵袭的影响。同时检测细胞基质金属蛋白酶（MMP）-2/9及p38/ERK/JNK信号通路相关分子的表达水平。通过注射重组人CyPA建立孕鼠模型，测定孕鼠血压、白蛋白/肌酐比值、胎鼠和胎盘重量。结果：CyPA能剂量依赖性地抑制HTR 8/SVneo细胞的迁移和侵袭，降低基质金属蛋白酶（MMP）-2/9和p38/ERK/JNK信号通路分子的表达。沉默CyPA可逆转上述效应。此外，CyPA可诱导妊娠小鼠出现PE样特征，并通过减少结合区面积破坏小鼠胎盘结构。CyPA通过下调MMP-2/9的表达和p38/ERK/JNK信号通路的活性，减弱小鼠胎盘滋养细胞的侵袭能力。
Aims: Numerous studies suggest that excessive maternal inflammation and defective extravillous trophoblast (EVT) invasion could contribute to the development of preeclampsia (PE), but the underlying mechanism remains unclear. Some evidence suggests that CyPA is elevated in PE. This research aims to investigate the effect of recombinant human CyPA on trophoblast migration and invasion both in vitro and in vivo.Materials and methods: We detected the expression and localization of CyPA in human placenta and explored the effects of CyPA on cell migration and invasion on HTR8/SVneo cell. Additionally, the expression levels of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway were detected. We established a mouse model by injecting pregnant mice with recombinant human CyPA and measured blood pressure, albumin/creatinine ratio, fetal and placenta weight of mice. Moreover, we examined the placental histology and MMP-2/9 and p38/ERK/JNK expression.Key findings: Our results showed that CyPA inhibited the migration and invasion of HTR8/SVneo cells in a dose-dependent manner, decreasing the expression of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway. Silencing CyPA could reverse the above effects. Moreover, CyPA could induce PE-like features in pregnant mice and disrupt the structure of the mouse placenta by reducing the junctional zone area. CyPA attenuated the trophoblast invasiveness in mice placenta by downregulating MMP-2/9 expression and p38/ERK/JNK pathway activity.Significance: We proposed that CyPA could inhibit trophoblast migration and invasion both in vitro and in vivo, which was involved in PE development.