title: Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta.
abstract: Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG). These anti-angiogenic factors cause hypertension and multi-organ injury. Pravastatin decreases placental secretion of sFlt-1 in vitro and is currently being examined in clinical trials as a potential treatment for preeclampsia. However, it is possible that different classes of statins may be more potent at decreasing sFlt-1 secretion. We compared the relative potency of three different generations of statins on sFlt-1 and sENG secretion from human endothelial cells, trophoblast cells, and placenta explants.
  
  
  
  We performed functional experiments using primary human umbilical vein endothelial cells, trophoblast cells and preterm preeclamptic placental explants to assess the affect of simvastatin, rosuvastatin and pravastatin on sFlt-1 and sENG secretion and compared the relative potency of each statin at reducing these factors (Inhibitory Concentration 50). Furthermore we assessed the effect of each statin on the antioxidant and cytoprotective enzyme, heme-oxygenase 1.
  
  
  
  All statins reduced sFlt-1 secretion from endothelial cells, trophoblasts and preterm preeclamptic placental explants. Simvastatin was the most potent inhibitor of sFlt-1 secretion from endothelial cells (IC 50 3.2 μM), trophoblast cells (IC 50 61.4 μM) and placental explants. Simvastatin was 28 times and 3 times more potent at reducing sFlt-1 secretion from endothelial cells and 85 times and 33 times more potent at reducing sFlt-1 secretion from trophoblast cells than pravastatin or rosuvastatin respectively. All statins increased sENG secretion from endothelial cells however did not change secretion from placental explants. While all statins up-regulated heme-oxygenase 1 in endothelial cells, only simvastatin up-regulated its expression in placenta from patients with preterm preeclampsia.
  
  
  
  Simvastatin may be a more potent inhibitor of sFlt-1 secretion from endothelial cells, trophoblast cells and placenta from women with preterm preeclampsia than either pravastatin or rosuvastatin.
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia. Fiona.brownfoot@unimelb.edu.au.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Brownfoot
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Hastie
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Cannon
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
mesh_terms: D000071063:Endoglin / Q000187:drug effects; D005260:Female; D051547:Heme Oxygenase-1 / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D011225:Pre-Eclampsia / Q000188:drug therapy; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000187:drug effects* / Q000378:metabolism; D000068718:Rosuvastatin Calcium / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects*; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000187:drug effects / Q000378:metabolism
chemical_list: C064206:ENG protein, human; D000071063:Endoglin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011257:Pregnancy Proteins; D000068718:Rosuvastatin Calcium; D019821:Simvastatin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D017035:Pravastatin
keywords: Preeclampsia; Pregnancy; Soluble endoglin; Statins; sFlt-1