Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing, 400016, China.
J Physiol Biochem. 2019 Nov;75(4):475-487. doi: 10.1007/s13105-019-00700-9. Epub 2019 Aug 10.
Preeclampsia (PE) is a hypertensive disease associated with increased endothelial cell dysfunction caused by systemic oxidative stress. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that are upregulated in several types of cancer. However, its role in PE remains unclear. In this study, we found that ACTN4 was localized in placenta vascular endothelial cells (ECs), and its expression was downregulated in primary human umbilical vein endothelial cells (HUVECs) from severe preeclamptic patients compared to that in HUVECs from normotensive pregnant women. ACTN4 expression was also decreased in normotensive HUVECs treated with HO. Downregulation of ACTN4 by siRNA or HO treatment promoted normotensive HUVEC apoptosis and increased p38-MAPK phosphorylation along with elevated levels of p53 phosphorylation, caspase cascade proteins, and bax and repressed expression of bcl-2. Conversely, upregulation of ACTN4 in PE HUVECs significantly inhibited apoptosis and decreased p38-MAPK phosphorylation compared to that of the PE HUVEC controls. In addition, overexpression of ACTN4 in normotensive HUVECs attenuated HO treatment-induced apoptosis with decreased p53 phosphorylation, caspase cascade, and bax expression levels and increased expression of bcl-2 compared to that of only HO treatment. Moreover, the suppression of ACTN4 induced apoptosis, which could be blocked by the p38-MAPK inhibitor SB202190. Collectively, these results demonstrate that dysregulated ACTN4 expression may be associated with PE due to its effects on endothelial cell apoptosis via the p38-MAPK/p53 apoptosis pathway.
子痫前期（PE）是一种与全身氧化应激引起的内皮细胞功能障碍增加相关的高血压疾病。α-辅肌动蛋白-4（ACTN4）是肌动蛋白交联蛋白α-辅肌动蛋白家族的成员，在几种类型的癌症中上调。然而，其在 PE 中的作用尚不清楚。在这项研究中，我们发现 ACTN4 定位于胎盘血管内皮细胞（EC），与正常妊娠妇女的脐静脉内皮细胞（HUVEC）相比，严重子痫前期患者的原代 HUVEC 中其表达下调。正常妊娠 HUVEC 用 HO 处理后，ACTN4 的表达也降低。用 siRNA 下调或 HO 处理下调 ACTN4 可促进正常 HUVEC 凋亡，并增加 p38-MAPK 磷酸化，同时升高 p53 磷酸化、caspase 级联蛋白、bax 的水平，并抑制 bcl-2 的表达。相反，与 PE HUVEC 对照相比，PE HUVEC 中 ACTN4 的上调可显著抑制凋亡并降低 p38-MAPK 磷酸化。此外，与仅用 HO 处理相比，在正常 HUVEC 中过表达 ACTN4 可减轻 HO 处理诱导的凋亡，降低 p53 磷酸化、caspase 级联和 bax 的表达水平，并增加 bcl-2 的表达。此外，ACTN4 的抑制诱导凋亡，这可被 p38-MAPK 抑制剂 SB202190 阻断。总之，这些结果表明，由于 ACTN4 表达的失调可能通过 p38-MAPK/p53 凋亡途径影响内皮细胞凋亡，因此其与 PE 有关。
