Objective: Despite advancements in our understanding of preeclampsia (preE), there are currently no effective therapies to prevent the disease. Pravastatin shows promise by attenuating pathophysiologic processes associated with preE such as decreased cytotrophoblast (CTB) migration, aberrant angiogenesis, and increased oxidative stress. This study assesses the effects of pravastatin on hyperglycemia-induced CTB dysfunction and its use as a potential drug for the prevention of preE. Methods: Human CTB cells were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 hours. Some cells were pretreated with pravastatin (1ug/mL), while others were cotreated with pravastatin and glucose. Expression of urokinase plasminogen activator ( uPA ), plasminogen activator inhibitor 1 ( PAI-1 ), proliferating cell nuclear antigen ( PCNA ), and p38 MAPK phosphorylation were measured by western blot. uPA and PAI-1 mRNA was measured by quantitative PCR. Angiogenic (vascular endothelial growth factor [ VEGF ], placenta growth factor [ PlGF ]) and antiangiogenic factors (soluble fms-like tyrosine kinase-1 [ sFlt-1 ], soluble endoglin [ sEng ]) were measured by enzyme-linked immunosorbent assay (ELISA) kits. Statistical comparisons were performed using analysis of variance with Duncans post-hoc test. Results: The hyperglycemia-induced downregulation of uPA was attenuated in CTB cells pretreated with pravastatin at glucose levels <200 mg/dL, and cotreated at glucose levels <300 mg/dL (p>0.05). The hyperglycemia-induced downregulation of PAI-1 , PCNA, VEGF, and PlGF and the upregulation of p38 phosphorylation, sENG , and sFlt-1 were also attenuated in both pretreatment and cotreatment samples in all groups regardless of glucose dose (p>0.05). Conclusions: Pravastatin mitigates the CTB cell dysfunction initiated by hyperglycemic conditions by attenuating the glucose-induced down-regulation of uPA , PAI-1 , and PCNA expression, up-regulation of p38 phosphorylation, downregulation of VEGF and PlGF, and upregulation of sFLT-1 and sEng, thereby decreasing the stress signaling response that normally leads to abnormal placentation, and is associated with the development of preE in pregnancy. Key words: Preeclampsia; Diabetes; Pregnancy
