Department of Physiology, Harbin Medical University, Harbin, 150081, China.
Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
Free Radic Biol Med. 2023 Nov 1;208:759-770. doi: 10.1016/j.freeradbiomed.2023.09.030. Epub 2023 Sep 27.
Preeclampsia 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.
Our 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 CoCl-induced superoxide production, but also prevented CoCl-induced reduction of SOD activity and SOD1 expression. In addition, apelin-13 suppressed CoCl-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.
Decrease 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.
子痫前期是一种胎盘诱导的综合征，具有多种临床表现，目前尚无治愈方法。氧化应激是胎盘功能障碍的有力诱导因素。阿皮素受体（APJ）系统是一种多效途径，具有在子痫前期进行治疗靶向的潜力。本研究检测了子痫前期患者循环阿皮素水平和胎盘 APJ 表达的变化，并探讨了阿皮素/APJ 系统是否可以通过 PI3K/AKT 信号通路保护胎盘滋养层免受缺氧诱导的氧化应激损伤。
我们的结果证实，子痫前期妇女的母体外周血阿皮素浓度增加，但子痫前期胎盘 APJ 表达减少。阿皮素-13 处理不仅特异性减弱 CoCl 诱导的超氧化物产生，而且还防止 CoCl 诱导的 SOD 活性和 SOD1 表达减少。此外，阿皮素-13 通过增加 bcl-2/bax 比值的表达和减少胎盘滋养层中活性 caspase-3 的表达来抑制 CoCl 诱导的凋亡。此外，我们发现阿皮素-13 与 APJ 结合激活了 PI3K 和 AKT 激酶，而 PI3K 激酶抑制剂显著阻断了阿皮素-13 在胎盘滋养层中的抗氧化作用。
胎盘 APJ 表达的减少与子痫前期中氧化应激诱导的胎盘功能障碍有关，而循环中阿皮素的增加可能是区分子痫前期患者和健康孕妇的一个较为成功的标志物。抑制超氧化物产生和 caspase-3 切割，以及上调 SOD 活性/表达和 bcl-2/bax 比值，可能是阿皮素-13/APJ 保护胎盘滋养层免受氧化应激损伤的潜在分子机制。
