The Hospital for Sick Children, Program in Developmental and Stem Cell Biology, Toronto, Ontario, Canada.
Mol Cell Proteomics. 2011 Dec;10(12):M111.012526. doi: 10.1074/mcp.M111.012526. Epub 2011 Oct 10.
Preeclampsia (PE) adversely impacts ~5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distinguish the trophoblast and endothelial cells of the placenta in the mouse; (2) to translate this marker set to human via the Human Protein Atlas database; and (3) to utilize the validated human trophoblast markers to identify subgroups of human preeclampsia. To achieve these goals, plasma membrane proteins at the blood tissue interfaces were extracted from placentas using intravascular silica-bead perfusion, and then identified using shotgun proteomics. We identified 1181 plasma membrane proteins, of which 171 were enriched at the maternal blood-trophoblast interface and 192 at the fetal endothelial interface with a 70% conservation of expression in humans. Three distinct molecular subgroups of human preeclampsia were identified in existing human microarray data by using expression patterns of trophoblast-enriched proteins. Analysis of all misexpressed genes revealed divergent dysfunctions including angiogenesis (subgroup 1), MAPK signaling (subgroup 2), and hormone biosynthesis and metabolism (subgroup 3). Subgroup 2 lacked expected changes in known preeclampsia markers (sFLT1, sENG) and uniquely overexpressed GNA12. In an independent set of 40 banked placental specimens, GNA12 was overexpressed during preeclampsia when co-incident with chronic hypertension. In the current study we used a novel translational analysis to integrate mouse and human trophoblast protein expression with human microarray data. This strategy identified distinct molecular pathologies in human preeclampsia. We conclude that clinically similar preeclampsia patients exhibit divergent placental gene expression profiles thus implicating divergent molecular mechanisms in the origins of this disease.
子痫前期（PE）会对约 5%的妊娠产生不利影响。尽管进行了广泛的研究，但仍未出现一致的生物标志物或治疗方法，这表明不同的分子机制可能导致临床相似的疾病。为了解决这个问题，我们进行了一项蛋白质组学研究，主要有三个目标：（1）鉴定一组可区分胎盘滋养层细胞和内皮细胞的细胞表面标志物；（2）通过人类蛋白质图谱数据库将该标志物集转化为人类；（3）利用验证过的人类滋养层细胞标志物来鉴定人类子痫前期的亚组。为了实现这些目标，我们使用血管内硅珠灌注从胎盘提取血管组织界面的质膜蛋白，然后使用 shotgun 蛋白质组学进行鉴定。我们鉴定了 1181 种质膜蛋白，其中 171 种在母体血液-滋养层界面富集，192 种在胎儿内皮界面富集，在人类中表达水平保持 70%的一致性。通过使用富含滋养层蛋白的表达模式，在现有的人类微阵列数据中，我们鉴定了 3 个人类子痫前期的不同分子亚组。对所有表达异常基因的分析揭示了血管生成（亚组 1）、MAPK 信号（亚组 2）和激素生物合成和代谢（亚组 3）的不同功能障碍。亚组 2 缺乏已知子痫前期标志物（sFLT1、sENG）的预期变化，并且独特地过表达 GNA12。在 40 个已保存胎盘标本的独立样本中，当与慢性高血压同时发生时，GNA12 在子痫前期中过表达。在本研究中，我们使用一种新的转化分析方法将小鼠和人类滋养层蛋白表达与人类微阵列数据整合在一起。这种策略鉴定了人类子痫前期的不同分子病理学。我们得出结论，临床相似的子痫前期患者表现出不同的胎盘基因表达谱，这表明该疾病的起源存在不同的分子机制。
