title: Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia.
abstract: Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta.
  
  
  
  Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean  ±  standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value < .05 was considered statistically significant.
  
  
  
  The sFlt-1 + Pravastatin mice had significantly higher placental protein concentrations of prosurvival/ antiapoptotic factors (activating transcription factor 2, pp38, phosphorylated c-jun N-terminal kinase, and phosphorylated extracellular signal-regulated kinase) and of heat-shock protein 27 and signal transducer and activator of transcription 3, 2 factors crucial for embryonic and placental development during oxidative stress, compared to sFlt-1 mice (P  <  .05) and similar to the mFc control group. No differences were noted in substrates of the proapoptotic pp53 pathway.
  
  
  
  Pravastatin ability to prevent preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia.
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA afsaad@utmb.edu.
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Saad
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Zaid M
authors.initials: ZM
authors.lastname: Diken
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Talar B
authors.initials: TB
authors.lastname: Kechichian
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Clark
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Gayle L
authors.initials: GL
authors.lastname: Olson
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Saade
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Maged M
authors.initials: MM
authors.lastname: Costantine
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism*; D017035:Pravastatin / Q000008:administration & dosage*; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000517:prevention & control; D011247:Pregnancy; D050796:STAT3 Transcription Factor / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D017035:Pravastatin
keywords: MAPK; placenta; pravastatin; preeclampsia; stress-induced survival