Plasma cross-gestational sphingolipidomic analyses reveal potential first trimester biomarkers of preeclampsia.
Plasma cross-gestational sphingolipidomic analyses reveal potential first trimester biomarkers of preeclampsia.
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DOI：
10.1371/journal.pone.0175118
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Morris AJ
中科院分区：
文献类型：
--
作者：
Dobierzewska A;Soman S;Illanes SE;Morris AJ
子痫前期是一种妊娠期疾病，主要表现为妊娠后期的高血压、蛋白尿和全身水肿。PE是孕产妇和胎儿发病和死亡的主要原因，占全球所有早产的近40%。具有生物活性的鞘脂是参与PE发病机制的关键分子，其特征在于母体血管生成失衡和代谢综合征症状。本研究的目的是比较先兆子痫（PE）与正常血压对照（CTL）受试者母体血浆中循环生物活性鞘脂的跨妊娠概况，目的是确定鞘脂作为PE早期预测疾病的候选妊娠早期生物标志物。在每例患者的妊娠早期、中期和晚期（妊娠11-14周、22-24周和32-36周）对患者进行前瞻性队列采样。采用回顾性分层研究设计定量母体血浆中不同类别的鞘脂。我们采用反相高效液相色谱-串联质谱法用于测定不同鞘脂分子种类的HPLC-ESI-MS/MS方法来自PE的人血浆跨妊娠样本中的神经酰胺（1-磷酸鞘氨醇（S1 P）、1-磷酸二氢鞘氨醇（DH-S1 P）、鞘磷脂（SM）和神经酰胺（Cer））（n = 7，21个妊娠期血浆样本）和CTL（n = 7，21个妊娠期血浆样本）患者。对照组和先兆子痫患者组的血管生成S1 P血浆水平在整个妊娠期没有显著变化。PE患者中孕中期血浆中DH-S1 P显著低于其孕早期，这可能导致PE中观察到的内皮屏障降低。在整个妊娠期间，对照和PE受试者血浆中的主要神经酰胺物质（Cer 16：0和Cer 24：0）倾向于上调。与妊娠匹配对照样本相比，PE患者妊娠早期血浆中丰度较低的血浆神经酰胺物质（Cer 14：0）水平显著较低（p = 0.009）。在整个妊娠期间，对照妊娠中主要血浆鞘磷脂物质（SM 16：0、SM 18：1和SM 24：0）往往较高。然而，在PE患者中，SM 16：0、SM 18：0和SM 18：1在整个妊娠期显示出显著上调，表明鞘磷脂的致动脉粥样硬化特性，特别是SM 18：0对疾病发展的潜在贡献。此外，两种主要鞘磷脂SM 16：0和SM 18：0在PE患者的前三个月血浆中显著低于相应对照的前三个月样本（分别为p = 0.007和p = 0.002）。对先兆子痫和血压正常妇女的母体血浆进行跨妊娠分析，确定了这两组之间主要鞘脂（DH-S1 P、鞘磷脂和神经酰胺）的生化特征的差异。此外，孕早期母体血浆鞘脂（Cer 14：0，SM 16：0和SM 18：0）可能在未来作为PE发生和发展的早期生物标志物。
Preeclampsia (PE) is a gestational disorder, manifested in the second half of pregnancy by maternal hypertension, proteinuria and generalized edema. PE is a major cause of maternal and fetal morbidity and mortality, accounting for nearly 40% of all premature births worldwide. Bioactive sphingolipids are emerging as key molecules involved in etiopathogenesis of PE, characterized by maternal angiogenic imbalance and symptoms of metabolic syndrome. The aim of this study was to compare the cross-gestational profile of circulating bioactive sphingolipids in maternal plasma from preeclamptic (PE) versus normotensive control (CTL) subjects with the goal of identifying sphingolipids as candidate first trimester biomarkers of PE for early prediction of the disease. A prospective cohort of patients was sampled at the first, second and third trimester of pregnancy for each patient (11–14, 22–24, and 32–36 weeks´ gestation). A retrospective stratified study design was used to quantify different classes of sphingolipids in maternal plasma. We used a reverse-phase high-performance liquid chromatography-tandem mass spectrometry (HPLC-ESI-MS/MS) approach for determining different sphingolipid molecular species (sphingosine-1-phosphate (S1P), dihydro-sphingosine-1-phosphate (DH-S1P), sphingomyelins (SM) and ceramides (Cer)) in cross-gestational samples of human plasma from PE (n = 7, 21 plasma samples across pregnancy) and CTL (n = 7, 21 plasma samples across pregnancy) patients. Plasma levels of angiogenic S1P did not change significantly in control and in preeclamptic patients´ group across gestation. DH-S1P was significantly decreased in second trimester plasma of PE patients in comparison to their first trimester, which could contribute to reduced endothelial barrier observed in PE. The major ceramide species (Cer 16:0 and Cer 24:0) tended to be up-regulated in plasma of control and PE subjects across gestation. The levels of a less abundant plasma ceramide species (Cer 14:0) were significantly lower in first trimester plasma of PE patients when compared with their gestational-matched control samples (p = 0.009). Major plasma sphingomyelin species (SM 16:0, SM 18:1 and SM 24:0) tended to be higher in control pregnancies across gestation. However, in PE patients, SM 16:0, SM 18:0 and SM 18:1 showed significant up-regulation across gestation, pointing to atherogenic properties of the sphingomyelins and particularly the potential contribution of SM 18:0 to the disease development. In addition, two major sphingomyelins, SM 16:0 and SM 18:0, were significantly lower in first trimester plasma of PE patients versus first trimester samples of respective controls (p = 0.007 and p = 0.002, respectively). Cross-gestational analysis of maternal plasma of preeclamptic and normotensive women identifies differences in the biochemical profile of major sphingolipids (DH-S1P, sphingomyelins and ceramides) between these two groups. In addition, first trimester maternal plasma sphingolipids (Cer 14:0, SM 16:0 and SM 18:0) may serve in the future as early biomarkers of PE occurrence and development.