Apelin/APJ system protects placental trophoblasts from hypoxia-induced oxidative stress through activating PI3K/Akt signaling pathway in preeclampsia
Apelin/APJ system protects placental trophoblasts from hypoxia-induced oxidative stress through activating PI3K/Akt signaling pathway in preeclampsia
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DOI：
10.1016/j.freeradbiomed.2023.09.030
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发表时间：
2023-10-01
影响因子：
7.4
通讯作者：
Zhu，Hui
中科院分区：
文献类型：
--
作者：
Ye，Lingyu;Huang，Yujia;Zhu，Hui
研究背景子痫前期是一种胎盘诱发的综合征，临床表现多样，目前尚无治愈方法。氧化应激是胎盘功能障碍的一个强有力的诱导物。爱帕琳受体（APJ）系统是一种多效性途径，具有治疗先兆子痫的潜在靶向作用。本研究探讨了子痫前期患者循环中apelin水平和胎盘APJ表达的变化，并探讨了apelin/APJ系统是否可以通过PI 3 K/AKT信号通路保护胎盘滋养层细胞免受缺氧诱导的氧化应激损伤。Apelin-13处理不仅特异性地减弱了CoCl 2诱导的超氧化物产生，而且还防止了CoCl 2诱导的SOD活性和SOD 1表达的降低。此外，apelin-13通过增加胎盘滋养层细胞中bcl-2/bax比值的表达和降低活性caspase-3的表达来抑制CoCl 2诱导的细胞凋亡。此外，我们发现apelin-13结合APJ激活PI 3 K和AKT激酶，并且PI 3 K激酶的抑制显著阻断apelin-13在胎盘滋养层细胞中的抗氧化作用。并且增加的循环Apelin可能是区分先兆子痫受试者与健康孕妇的适度成功的标志物。Apelin-13/APJ通过抑制超氧化物歧化酶（SOD）的产生和caspase-3的裂解，上调SOD活性/表达和bcl-2/bax比值，可能是其保护胎盘滋养细胞免受氧化应激损伤的潜在分子机制。
BackgroundPreeclampsia is a placentally induced syndrome with diverse clinical presentation that currently has no cure. Oxidative stress is a potent inducer of placental dysfunction. The apelin receptor (APJ) system is a pleiotropic pathway with a potential for therapeutic targeting in preeclampsia. This study examines the alteration of circulating apelin levels and placental APJ expression in preeclampsia and investigates whether apelin/APJ system can protect placental trophoblast from hypoxia-induced oxidative stress injury through PI3K/AKT signaling pathway.ResultsOur results confirmed that maternal apelin concentration was increased in women with preeclampsia, but APJ expression was reduced in the preeclamptic placentas. Apelin-13 treatment not only specifically attenuated CoCl2-induced superoxide production, but also prevented CoCl2-induced reduction of SOD activity and SOD1 expression. In addition, apelin-13 suppressed CoCl2-induced apoptosis by increasing the expression of bcl-2/bax ratio and by decreasing the expression of active caspase-3 in placental trophoblasts. Furthermore, we found that apelin-13 binding APJ activated the PI3K and AKT kinases and inhibition of PI3K kinase significantly blocked the anti-oxidative effects of apelin-13 in placental trophoblasts.ConclusionsDecrease of placental APJ expression is associated with oxidative stress-induced placental dysfunction in preeclampsia, and increased circulating apelin could be a moderately successful marker to differentiate subjects with preeclampsia from healthy pregnant women. Inhibition of superoxide production and caspase-3 cleavage, together with upregulation of SOD activity/expression and bcl-2/bax ratio, could be the potential molecular mechanisms by which apelin-13/APJ protects placental trophoblasts from oxidative stress injury.