Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia
Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia
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DOI：
10.1080/15548627.2015.1034414
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发表时间：
2015-04-01
期刊：
影响因子：
13.3
通讯作者：
Caniggia, Isabella
中科院分区：
文献类型：
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作者：
Melland-Smith, Megan;Ermini, Leonardo;Caniggia, Isabella
包括神经酰胺在内的生物活性鞘磷脂通过调节细胞的死亡和存活而参与多种病理生理过程。本研究的目的是研究神经酰胺在子痫前期中的代谢，这是一种以氧化应激为特征的严重妊娠紊乱，并增加滋养层细胞死亡和自噬。用串联质谱仪测定的孕妇外周血和胎盘神经酰胺水平在妊娠合并先兆子痫时升高。胎盘神经酰胺的增加是由于高丝氨酸棕榈酰基转移酶活性导致更多的从头合成，以及通过TGFB3诱导的E2F4转录抑制导致ASAH1表达减少而减少溶酶体的分解。SMPD1活性降低；因此，SMPD1对神经鞘蛋白的降解不会导致先兆子痫患者神经酰胺水平升高。氧化应激引起绒毛外植体和滋养层细胞神经酰胺水平和酸性水解酶表达的类似变化。MALDI成像质谱仪定位于妊娠合并子痫前期胎盘滋养细胞层和合体结节中神经酰胺的增加。ASAH1抑制或神经酰胺处理通过BOK-MCL1变阻器向死亡前BOK的转变诱导人滋养层细胞的自噬。药物抑制怀孕小鼠的ASAH1活性导致胎盘神经酰胺含量增加，胎盘异常，胎儿生长减慢，并通过BOK-MCL1系统的类似变化增加自噬。我们的结果表明，氧化应激诱导的溶酶体水解酶活性降低与从头合成增加相结合，导致神经酰胺超载，导致滋养层细胞自噬增加，典型的先兆子痫是一种鞘磷脂储存障碍。
Bioactive sphingolipids including ceramides are involved in a variety of pathophysiological processes by regulating cell death and survival. The objective of the current study was to examine ceramide metabolism in preeclampsia, a serious disorder of pregnancy characterized by oxidative stress, and increased trophoblast cell death and autophagy. Maternal circulating and placental ceramide levels quantified by tandem mass spectrometry were elevated in pregnancies complicated by preeclampsia. Placental ceramides were elevated due to greater de novo synthesis via high serine palmitoyltransferase activity and reduced lysosomal breakdown via diminished ASAH1 expression caused by TGFB3-induced E2F4 transcriptional repression. SMPD1 activity was reduced; hence, sphingomyelin degradation by SMPD1 did not contribute to elevated ceramide levels in preeclampsia. Oxidative stress triggered similar changes in ceramide levels and acid hydrolase expression in villous explants and trophoblast cells. MALDI-imaging mass spectrometry localized the ceramide increases to the trophophoblast layers and syncytial knots of placentae from pregnancies complicated by preeclampsia. ASAH1 inhibition or ceramide treatment induced autophagy in human trophoblast cells via a shift of the BOK-MCL1 rheostat toward prodeath BOK. Pharmacological inhibition of ASAH1 activity in pregnant mice resulted in increased placental ceramide content, abnormal placentation, reduced fetal growth, and increased autophagy via a similar shift in the BOK-MCL1 system. Our results reveal that oxidative stress-induced reduction of lysosomal hydrolase activities in combination with elevated de novo synthesis leads to ceramide overload, resulting in increased trophoblast cell autophagy, and typifies preeclampsia as a sphingolipid storage disorder.