Abstract:
Environmental changes can trigger endoplasmic reticulum (ER) stress and misfolded protein accumulation, potentially leading to pre-eclampsia (PE). Amyloid-β (Aβ) is a crucial misfolded protein that can overactivate autophagy. Our study assessed the expression of Aβ1-42 and autophagic activity in PE placental tissues and trophoblasts under ER stress. Placental tissues were surgically collected from normal pregnant women (NP) and pregnant women with late-onset PE (LOPE) delivering through cesarean section. The expression levels of Aβ1-42 were detected in both PE and NP placental tissues, as well as in tunicamycin (TM)-induced HTR-8/SVneo cells. Autophagy-related proteins, such as Beclin-1, the ratio of LC3-II to LC3-I, ATG5, and SQSTM1/p62 in the placental tissues and HTR-8/SVneo cells were measured by Western blot. The number and morphology of autophagosomes were observed using transmission electron microscopy (TEM). Potential targets associated with the unfolded protein response (UPR) in the placental tissues of NP and PE cases were screened using PCR Arrays. The misfolded protein was significantly upregulated in the PE group. In both PE placental tissues and TM-induced HTR-8/SVneo cells, not only was Aβ1-42 upregulated, but also Beclin-1, ATG5, and LC3BII/I were significantly increased, accompanied by an increase in autophagosome count, while SQSTM1/P62 was downregulated. A total of 17 differentially expressed genes (DEGs) associated with the UPR were identified, among which elevated calnexin (CANX) was validated in the placenta from both PE and TM-induced HTR-8/SVneo cells. Autophagy is significantly upregulated in PE cases due to ER stress-induced Aβ1-42 accumulation, likely mediated by autophagy-related proteins involved in the UPR.
摘要:
环境变化可引发内质网(ER)应激和错误折叠的蛋白质积累,可能导致先兆子痫(PE)。淀粉样蛋白-β(Aβ)是一种重要的错误折叠蛋白,可以过度激活自噬。我们的研究评估了ER应激下PE胎盘组织和滋养细胞中Aβ1-42的表达和自噬活性。通过手术从正常孕妇(NP)和通过剖宫产分娩的晚发型PE(LOPE)孕妇中收集胎盘组织。在PE和NP胎盘组织中均检测到Aβ1-42的表达水平,以及在衣霉素(TM)诱导的HTR-8/SVneo细胞中。自噬相关蛋白,例如Beclin-1,LC3-II与LC3-I的比率,通过Western印迹测量胎盘组织和HTR-8/SVneo细胞中的ATG5和SQSTM1/p62。利用透射电子显微镜(TEM)观察自噬体的数量和形态。使用PCR阵列筛选与NP和PE病例的胎盘组织中的未折叠蛋白反应(UPR)相关的潜在靶标。错误折叠的蛋白质在PE组中显著上调。在PE胎盘组织和TM诱导的HTR-8/SVneo细胞中,Aβ1-42不仅上调,而且Beclin-1、ATG5和LC3BII/I也显著增加,伴随着自噬体数量的增加,而SQSTM1/P62下调。共鉴定出17个与UPR相关的差异表达基因(DEGs),其中在PE和TM诱导的HTR-8/SVneo细胞的胎盘中验证了calnexin(CANX)升高。由于内质网应激诱导的Aβ1-42积累,自噬在PE病例中显著上调,可能由参与UPR的自噬相关蛋白介导。