TY - JOUR
T1 - Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia
AU - Saad, Antonio
AU - Diken, Zaid M.
AU - Kechichian, Talar B.
AU - Clark, Shannon
AU - Olson, Gayle
AU - Saade, George
AU - Costantine, Maged
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
KW - MAPK
KW - placenta
KW - pravastatin
KW - preeclampsia
KW - stress-induced survival
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U2 - 10.1177/1933719116648218
DO - 10.1177/1933719116648218
M3 - Article
C2 - 27170663
AN - SCOPUS:84991383940
SN - 1933-7191
VL - 23
SP - 1593
EP - 1599
JO - Reproductive Sciences
JF - Reproductive Sciences
IS - 11
ER -