Department of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
Int J Mol Med. 2019 May;43(5):1939-1950. doi: 10.3892/ijmm.2019.4129. Epub 2019 Mar 12.
Preeclampsia (PE) is a pathological condition that manifests during pregnancy as the occurrence of an abnormal urine protein level and increased blood pressure due to inadequate cytotrophoblast invasion. To elucidate the mechanism underlying PE, the present study primarily focused on the regulatory effects and mechanism of the G protein γ 7 (GNG7) on placental cytotrophoblasts in a rat PE model. Initially, the PE model was established with 45 specific pathogen‑free Sprague‑Dawley rats (30 females and 15 males). The expression patterns of GNG7, 4E‑binding protein 1 (4E‑BP1), phosphoprotein 70 ribosomal protein S6 kinase (p70S6K) and mammalian target of rapamycin (mTOR) were examined in the PE rats. Placental cytotrophoblasts isolated from normal and PE rats were treated with a small interfering RNA against GNG7, mTOR signaling pathway activator (HIV‑1 Tat) or inhibitor (rapamycin). Following treatment, cell proliferation, differentiation and apoptosis were evaluated, and mTOR signaling pathway‑related factors (4E‑BP1, p70S6K and mTOR), cell proliferation‑related factors (vascular endothelial growth factor and transforming growth factor‑β1), differentiation‑related factors [activator protein‑2 (AP‑2)α and AP‑2γ], and apoptosis‑related factors [B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein] were determined. Finally, soluble fms‑like tyrosine kinase 1 (sFlt‑1) and soluble endoglin (sEng) levels were measured via enzyme‑linked immunosorbent assay. Initially, the mTOR signaling pathway was inactivated in the placental tissues and cytotrophoblasts in the PE rats. Silencing GNG7 reduced the levels of sFlt‑1 and sEng and activated the mTOR signaling pathway. Silencing of GNG7 or activation of the mTOR signaling pathway enhanced cell proliferation and differentiation, but inhibited the apoptosis of placental cytotrophoblasts in the PE rats. Taken together, the results showed that GNG7 silencing repressed apoptosis and enhanced the proliferation and differentiation of placental cytotrophoblasts in PE rats through activation of the mTOR signaling pathway.
子痫前期(PE)是一种病理状况,表现为妊娠期间由于绒毛滋养细胞侵袭不足而导致异常尿蛋白水平和血压升高。为了阐明 PE 的发病机制,本研究主要集中在 G 蛋白 γ 7(GNG7)对大鼠 PE 模型胎盘绒毛滋养细胞的调节作用及其机制上。首先,用 45 只特定病原体无自由 Sprague-Dawley 大鼠(30 只雌性和 15 只雄性)建立 PE 模型。检查 PE 大鼠中 GNG7、4E 结合蛋白 1(4E-BP1)、磷酸化蛋白 70 核糖体蛋白 S6 激酶(p70S6K)和哺乳动物雷帕霉素靶蛋白(mTOR)的表达模式。从正常和 PE 大鼠中分离胎盘绒毛滋养细胞,用 GNG7 小干扰 RNA、mTOR 信号通路激活剂(HIV-1 Tat)或抑制剂(雷帕霉素)处理。处理后,评估细胞增殖、分化和凋亡,测定 mTOR 信号通路相关因子(4E-BP1、p70S6K 和 mTOR)、细胞增殖相关因子(血管内皮生长因子和转化生长因子-β1)、分化相关因子[激活蛋白-2(AP-2)α和 AP-2γ]和凋亡相关因子[B 细胞淋巴瘤 2(Bcl-2)和 Bcl-2 相关 X 蛋白]。最后,通过酶联免疫吸附试验测定可溶性 fms 样酪氨酸激酶 1(sFlt-1)和可溶性内皮糖蛋白(sEng)水平。最初,PE 大鼠胎盘组织和绒毛滋养细胞中的 mTOR 信号通路被失活。沉默 GNG7 降低了 sFlt-1 和 sEng 的水平并激活了 mTOR 信号通路。沉默 GNG7 或激活 mTOR 信号通路增强了 PE 大鼠胎盘绒毛滋养细胞的增殖和分化,但抑制了其凋亡。综上所述,结果表明 GNG7 沉默通过激活 mTOR 信号通路抑制凋亡,增强 PE 大鼠胎盘绒毛滋养细胞的增殖和分化。