Abstract P088: Pravastatin Protects Against Glucose-induced Anti-proliferative, Anti-invasive and Anti-angiogenic Milieu in Cytotrophoblasts
Objective: An increasing level of evidence supports the utility of pravastatin in prevention against preeclampsia (preE). We previously demonstrated that hyperglycemia induces cytotrophoblasts (CTBs) dysfunction characteristic of a preE-like phenotype. We sought to demonstrate the utility of pravastatin in rescuing CTBs from hyperglycemia induced dysfunction.
Methods: Human CTBs were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48h. Some cells were pretreated with pravastatin (1ug/mL) for 2h, while others were co-treated with pravastatin (1ug/mL) prior to glucose treatment. Some cells were treated with D-Mannitol. Cell migration was performed by Matrigel migration assay kit according to manufacturer protocol. Cell lysates were utilized to evaluate the expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), proliferating cell nuclear antigen (PCNA) and p38 MAPK phosphorylation by western blot. Levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and interleukin 6 (IL-6) were measured in culture media using ELISA kits. Statistical comparisons were performed using analysis of variance with Duncan’s post hoc test.
Results: Hyperglycemia inhibited CTBs migration, down-regulated uPA, PAI-1, PCNA and up-regulated p38 phosphorylation in CTBs treated with ≥150 mg/dL glucose compared to basal (100 mg/dL) (*p < 0.05 for each). Secretion of sFlt-1, sEng and IL-6 were increased while VEGF and PIGF were decreased in CTBs treated ≥150 mg/dl of glucose (*p < 0.05 for each). Both pravastatin pretreatment and co-treatment significantly rescued CTBs migration, up-regulated uPA, PAI-1, PCNA, down-regulated p38 phosphorylation, and corrected the angiogenic profile of CTBs (p < 0.05 for each). D-Mannitol had no effect on CTBs.
Conclusions: Pravastatin mitigates the hyperglycemia-induced dysfunction of CTBs by attenuating the glucose-induced anti-proliferative, anti-invasive and anti-angiogenic phenotype. These data should alleviate critical concerns regarding pravastatin use on CTBs development early in pregnancy and support the current research to use of pravastatin in preE prevention.
Author Disclosures: S.H. Afroze: None. K.B. Wesley: None. N. Drever: None. M.M. Costantine: None. S.R. Allen: None. D.C. Zawieja: None. T.J. Kuehl: None. M.N. Uddin: None.
- © 2015 by American Heart Association, Inc.