Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia

Reprod Sci. 2016 Nov;23(11):1593-1599. doi: 10.1177/1933719116648218. Epub 2016 May 11.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: MAPK; placenta; pravastatin; preeclampsia; stress-induced survival.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Disease Models, Animal
  • Female
  • HSP27 Heat-Shock Proteins / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Phosphorylation
  • Placenta / drug effects*
  • Placenta / metabolism*
  • Pravastatin / administration & dosage*
  • Pre-Eclampsia / metabolism*
  • Pre-Eclampsia / prevention & control
  • Pregnancy
  • STAT3 Transcription Factor / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism

Substances

  • HSP27 Heat-Shock Proteins
  • Hspb2 protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Flt1 protein, mouse
  • Vascular Endothelial Growth Factor Receptor-1
  • Pravastatin