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 H₂O₂. Downregulation of ACTN4 by siRNA or H₂O₂ 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 H₂O₂ treatment-induced apoptosis with decreased p53 phosphorylation, caspase cascade, and bax expression levels and increased expression of bcl-2 compared to that of only H₂O₂ 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.

中文翻译：

---

ACTN4的表达失调通过先兆子痫中p38-MAPK / p53细胞凋亡途径的激活而导致内皮细胞损伤。

子痫前期（PE）是一种高血压疾病，与全身性氧化应激引起的内皮细胞功能障碍增加有关。α-actinin-4（ACTN4）是肌动蛋白交联蛋白的α-actinin家族的成员，在几种类型的癌症中均被上调。但是，其在PE中的作用仍不清楚。在这项研究中，我们发现ACTN4位于胎盘血管内皮细胞（ECs）中，与正常血压孕妇的HUVECs相比，其表达在重度子痫前期患者的原代人脐静脉内皮细胞（HUVECs）中被下调。在用H ₂ O ₂处理的血压正常的HUVEC中ACTN4表达也降低。siRNA或H ₂ O ₂下调ACTN4该疗法可促进血压正常的HUVEC凋亡并增加p38-MAPK磷酸化，以及p53磷酸化，胱天蛋白酶级联蛋白和bax升高，并抑制bcl-2的表达。相反，与PE HUVEC对照相比，PE HUVEC中ACTN4的上调显着抑制了细胞凋亡并降低了p38-MAPK磷酸化。另外，在血压正常的HUVEC ACTN4的过表达减毒ħ ₂ ö ₂治疗诱导的细胞凋亡具有降低p53的磷酸，胱天蛋白酶级联反应，和bax表达水平和增加的BCL-2的表达相比，只有H的₂ ö ₂治疗。此外，抑制ACTN4诱导的凋亡可能被p38-MAPK抑制剂SB202190阻断。总的来说，这些结果表明ACTN4表达失调可能与PE有关，这是由于其通过p38-MAPK / p53凋亡途径对内皮细胞凋亡的影响。