title: Key players of the necroptosis pathway RIPK1 and SIRT2 are altered in placenta from preeclampsia and fetal growth restriction.
abstract: Preeclampsia (PE) and fetal growth restriction (FGR) are among the leading causes of perinatal morbidity and mortality. Placental insufficiency is central to these conditions. The mechanisms underlying placental insufficiency are poorly understood. Apoptosis has long been considered the only form of regulated cell death, recent research has identified an alternate process of programmed cell death known as necroptosis [1]. Necroptosis is distinct from apoptosis, relying on the deacetylase sirtuin-2 [2], receptor interacting kinases RIPK1 and 3, and the pseudokinase MLKL [3]. We aimed to determine whether these key necroptosis effector molecules were present in human placenta and whether they are differentially expressed in severe preterm (PT) PE and FGR.
  
  
  
  PT placentas from severe early onset (<34 weeks) PE (n = 30), FGR (n = 12) and control (18) pregnancies were collected. SIRT2 and RIPK1 localization and quantitation was determined by immunohistochemistry and western blot. Immunocytochemistry was used to detect SIRT2 and RIPK1 in trophoblastic debris from first trimester, term control and PE pregnancies. Expression of SIRT2, RIPK1, RIPK3 and MLKL was examined by qPCR.
  
  
  
  SIRT2 and RIPK1 were localized to the syncytiotrophoblast, villous leukocytes and vasculature in all PT placentas. A significant reduction in SIRT2 protein expression in both PE and FGR placentas was identified. RIPK1 mRNA expression was significantly increased in PE placentas. Immunofluorescence identified both SIRT2 and RIPK1 in the cytotrophoblast cytoplasm.
  
  
  
  We have identified the presence of activators of necroptosis in human placenta. Interestingly, there is differential expression in major pregnancy complications. We conclude necroptosis may contribute to placental pathophysiology that underlies serious pregnancy complications.
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia. Electronic address: nhannan@unimelb.edu.au.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Sally
authors.initials: S
authors.lastname: Beard
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Binder
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Onda
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Tuohey
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Manarangi
authors.initials: M
authors.lastname: De Silva
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
mesh_terms: D000328:Adult; D016923:Cell Death / Q000502:physiology*; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism; D055815:Young Adult
chemical_list: C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: Fetal growth restriction; Necroptosis; Preeclampsia