title: Antiphospholipid Antibodies Alter Cell-Death-Regulating Lipid Metabolites in First and Third Trimester Human Placentae.
abstract: OBJECTIVE
  Antiphospholipid antibodies (aPL) are maternal autoantibodies that increase the risk of a woman developing preeclampsia 10-fold. aPL are internalized into the syncytiotrophoblast and increase extrusion of necrotic trophoblast debris into the maternal blood. This necrotic trophoblast debris may trigger endothelial cell dysfunction contributing to the pathogenesis of preeclampsia. We hypothesize that aPL directly affect placental metabolism, leading to increased syncytiotrophoblast death.
  
  
  METHODS
  First and third trimester human placental explants were cultured with aPL, a control antibody, or media only, and placental conditioned culture media was examined by mass spectroscopy. Molecular targets of interest were investigated using qRTPCR and immunohistochemistry.
  
  
  RESULTS
  The levels of 79 and 132 metabolites, respectively, were altered due to the treatment of first and third trimester placental explants with aPL. These included ceramides and diacylglycerols, which play important roles in cell death regulatory pathways. Antiphospholipid antibodies also decreased the expression of protein kinase C-epsilon (PRKCE) in placental explants, possibly due to the disrupted balance between ceramides and diacylglycerols caused by aPL.
  
  
  CONCLUSIONS
  One mechanism by which aPL cause aberrant cell death in the syncytiotrophoblast in the first and third trimester is by disruption of placental lipid signaling and decreased expression of PRKCE.
authors: Department of Obstetrics & Gynaecology, The University of Auckland, Auckland, New Zealand.|Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors: Priyadarshini
authors: P
authors: Pantham
authors: The Maternal and Fetal Health Research Centre, St. Mary's Hospital, The University of Manchester, Manchester, UK.
authors: Alexander E P
authors: AE
authors: Heazell
authors: Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK.
authors: Graham
authors: G
authors: Mullard
authors: Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK.
authors: Paul
authors: P
authors: Begley
authors: Department of Obstetrics & Gynaecology, The University of Auckland, Auckland, New Zealand.
authors: Qi
authors: Q
authors: Chen
authors: Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK.
authors: Maria
authors: M
authors: Brown
authors: Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK.|Centre for Endocrinology and Diabetes, Institute of Human Development, The University of Manchester, Manchester, UK.|School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, UK.
authors: Warwick B
authors: WB
authors: Dunn
authors: Department of Obstetrics & Gynaecology, The University of Auckland, Auckland, New Zealand.
authors: Lawrence W
authors: LW
authors: Chamley
mesh_terms: D017152:Antibodies, Antiphospholipid / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D055432:Metabolomics; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000378:metabolism; D011263:Pregnancy Trimester, Third / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism*
chemical_list: D017152:Antibodies, Antiphospholipid; D051744:Protein Kinase C-epsilon
keywords: Antiphospholipid antibodies; apoptosis; ceramides; metabolomics; protein kinase C; syncytiotrophoblast