Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan; Department of Obstetrics and Gynecology, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan.
Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan.
Biomed Pharmacother. 2021 Jul;139:111591. doi: 10.1016/j.biopha.2021.111591. Epub 2021 Apr 14.
Preeclampsia is a severe gestational hypertensive disorder that occurs after 20 weeks' of gestation. It involves several maternal systems, such as cardiovascular, renal, coagulatory systems, and poses a major threat to the maternal and fetal health. Recent clinical evidence showed that aspirin is an effective preventative treatment for reducing the incidence of premature preeclampsia among high-risk pregnant women, however, the mechanism of drug action is not clear. miR-200 family has been shown to be associated with preeclampsia and upregulated in the plasma and placenta of preeclamptic patients. Here we revealed that miR-200 family inhibited trophoblast invasion and epithelial-mesenchymal transition (EMT) process by stimulating epithelial marker expression (E-cadherin and ZO-1) and repressing mesenchymal marker expression (ZEB1 and TGFβ1). Similarly, EMT markers in the placenta of preeclamptic patients showed higher E-cadherin and lower ZEB1 and TGF-β1 protein expression. Moreover, aspirin was shown to suppress miR-200 family and these miR-200 family-mediated cell functions, including cell invasion and EMT changes, were completely reversed. In conclusion, this study demonstrates the effect of miR-200 family on trophoblast invasion and EMT. For the first time, aspirin was shown to fully reverse miR-200-mediated trophoblast biology and act through the network signaling of TGF-β1/ZEB1/miR-200. These results provide a plausible mechanism explaining aspirin's effect on preeclampsia prevention and a therapeutic target for disease intervention.
子痫前期是一种严重的妊娠期高血压疾病，发生在妊娠 20 周后。它涉及多个母体系统，如心血管、肾脏、凝血系统，对母婴健康构成重大威胁。最近的临床证据表明，阿司匹林是一种有效预防高危孕妇早产子痫前期的治疗方法，但药物作用机制尚不清楚。miR-200 家族与子痫前期有关，并且在子痫前期患者的血浆和胎盘中有上调表达。在这里，我们揭示了 miR-200 家族通过刺激上皮标志物表达（E-钙黏蛋白和 ZO-1）和抑制间充质标志物表达（ZEB1 和 TGFβ1）来抑制滋养细胞侵袭和上皮-间质转化（EMT）过程。同样，子痫前期患者胎盘中的 EMT 标志物显示出更高的 E-钙黏蛋白和更低的 ZEB1 和 TGF-β1 蛋白表达。此外，阿司匹林被证明可以抑制 miR-200 家族及其介导的细胞功能，包括细胞侵袭和 EMT 变化，这些作用都可以被完全逆转。总之，本研究证明了 miR-200 家族对滋养细胞侵袭和 EMT 的影响。首次表明，阿司匹林可以完全逆转 miR-200 介导的滋养细胞生物学，并通过 TGF-β1/ZEB1/miR-200 的网络信号发挥作用。这些结果提供了一个合理的机制来解释阿司匹林预防子痫前期的作用，并为疾病干预提供了一个治疗靶点。
