Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
Eur Rev Med Pharmacol Sci. 2020 Dec;24(24):12955-12962. doi: 10.26355/eurrev_202012_24199.
The aim of this study was to explore the effects of pravastatin on oxidative stress and placental trophoblastic cell apoptosis in preeclampsia rats via the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway.
Experimental rats were randomly assigned into three groups, including control group (C group), model group (M group) and pravastatin group (P group). The rat model of preeclampsia was successfully established. Blood pressure, urinary protein and nitric oxide (NO) as well as oxidative stress indicators in rats were detected at 7, 14 and 21 d, respectively. The content of serum IL-6 was determined via enzyme-linked immunosorbent assay (ELISA). The messenger ribonucleic acid (mRNA) expression of IL-6 in the placenta of rats in each group was detected using quantitative polymerase chain reaction (qPCR). Western blotting (WB) was used to determine the protein expression level of STATs in the placental tissues of rats. In addition, cell counting kit (CCK)-8 assay was conducted to detect the proliferation of rat placental trophoblasts.
The content of serum NO was (14.32±2.32) μM in M group, (28.37±3.32) μM in C group and (22.54±3.12) μM in P group, respectively. It was significantly elevated in P group compared with M group (p<0.05). Blood pressure in M group was evidently higher than that in C group at 14 and 21 d (p<0.05). However, P group exhibited distinctly lower blood pressure than M group (p<0.05). No statistically significant differences were observed in the urinary protein of rats among all the three groups at 7 d (p>0.05). At 14 and 21 d, the content of urinary protein in M group was considerably higher than that in C group (p<0.05). However, P group had distinctly lower urinary protein content than M group (p<0.05). Compared with C group, the content of malondialdehyde (MDA) and advanced oxidation protein products (AOPP) rose significantly in M group, whereas the content of superoxide dismutase (SOD) declined remarkably (p<0.05). In comparison with M group, P group exhibited declined MDA and AOPP content and increased SOD content, with statistically significant differences between the two groups (p<0.05). The expression level of serum IL-6 in rats in M group was markedly higher than that in C group (p<0.05). Meanwhile, the expression level of serum IL-6 evidently declined in P group compared with M group (p<0.05). Compared with C group, the protein expressions of phosphorylated STAT1 (p-STAT1) and p-STAT3 were considerably up-regulated in M group (p<0.01). However, they decreased prominently in P group in comparison with M group (p<0.01). C group exhibited a remarkably worse proliferation ability of rat placental trophoblasts than C group (p<0.01). In comparison with M group, the proliferation ability of rat placental trophoblasts was evidently enhanced in P group (p<0.05). Flow cytometry results indicated that the apoptosis of trophoblastic cells increased significantly in M group compared with that in C group (p<0.01). However, it significantly declined in P group in comparison with M group (p<0.05).
Pravastatin can repress the IL-6/STAT3 signaling pathway to alleviate oxidative stress, improve preeclampsia and decrease the apoptosis of placental trophoblastic cells in preeclampsia rats.
本研究旨在探讨普伐他汀通过白细胞介素（IL）-6/信号转导和转录激活因子 3（STAT3）信号通路对先兆子痫大鼠氧化应激和胎盘滋养细胞凋亡的影响。
实验大鼠随机分为三组，包括对照组（C 组）、模型组（M 组）和普伐他汀组（P 组）。成功建立了先兆子痫大鼠模型。分别于第 7、14 和 21 天检测大鼠血压、尿蛋白和一氧化氮（NO）以及氧化应激指标。采用酶联免疫吸附试验（ELISA）测定血清 IL-6 含量。采用实时定量聚合酶链反应（qPCR）检测各组大鼠胎盘组织中 IL-6 的信使核糖核酸（mRNA）表达。采用 Western blot（WB）法测定大鼠胎盘组织中 STATs 的蛋白表达水平。此外，采用细胞计数试剂盒（CCK）-8 检测大鼠胎盘滋养细胞的增殖情况。
M 组血清 NO 含量为（14.32±2.32）μM，C 组为（28.37±3.32）μM，P 组为（22.54±3.12）μM，P 组明显高于 M 组（p<0.05）。M 组大鼠血压在 14 和 21 天明显高于 C 组（p<0.05），而 P 组明显低于 M 组（p<0.05）。三组大鼠在第 7 天的尿蛋白无统计学差异（p>0.05）。在 14 和 21 天，M 组大鼠尿蛋白含量明显高于 C 组（p<0.05），而 P 组明显低于 M 组（p<0.05）。与 C 组相比，M 组丙二醛（MDA）和高级氧化蛋白产物（AOPP）含量明显升高，而过氧化物歧化酶（SOD）含量明显降低（p<0.05）。与 M 组相比，P 组 MDA 和 AOPP 含量降低，SOD 含量升高，两组间差异有统计学意义（p<0.05）。M 组大鼠血清 IL-6 表达水平明显高于 C 组（p<0.05），而 P 组明显低于 M 组（p<0.05）。与 C 组相比，M 组磷酸化 STAT1（p-STAT1）和 p-STAT3 的蛋白表达明显上调（p<0.01），而 P 组明显下调（p<0.01）。与 C 组相比，M 组大鼠胎盘滋养细胞增殖能力明显下降（p<0.01），而 P 组大鼠胎盘滋养细胞增殖能力明显增强（p<0.05）。流式细胞术结果表明，与 C 组相比，M 组滋养细胞凋亡明显增加（p<0.01），而 P 组明显下降（p<0.05）。
普伐他汀可抑制 IL-6/STAT3 信号通路，减轻氧化应激，改善先兆子痫大鼠病情，降低胎盘滋养细胞凋亡。
