Abstract
BackgroundPreeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG). These anti-angiogenic factors cause hypertension and multi-organ injury. Pravastatin decreases placental secretion of sFlt-1 in vitro and is currently being examined in clinical trials as a potential treatment for preeclampsia. However, it is possible that different classes of statins may be more potent at decreasing sFlt-1 secretion. We compared the relative potency of three different generations of statins on sFlt-1 and sENG secretion from human endothelial cells, trophoblast cells, and placenta explants.MethodsWe performed functional experiments using primary human umbilical vein endothelial cells, trophoblast cells and preterm preeclamptic placental explants to assess the affect of simvastatin, rosuvastatin and pravastatin on sFlt-1 and sENG secretion and compared the relative potency of each statin at reducing these factors (Inhibitory Concentration 50). Furthermore we assessed the effect of each statin on the antioxidant and cytoprotective enzyme, heme-oxygenase 1.ResultsAll statins reduced sFlt-1 secretion from endothelial cells, trophoblasts and preterm preeclamptic placental explants. Simvastatin was the most potent inhibitor of sFlt-1 secretion from endothelial cells (IC 50 3.2 μM), trophoblast cells (IC 50 61.4 μM) and placental explants. Simvastatin was 28 times and 3 times more potent at reducing sFlt-1 secretion from endothelial cells and 85 times and 33 times more potent at reducing sFlt-1 secretion from trophoblast cells than pravastatin or rosuvastatin respectively.All statins increased sENG secretion from endothelial cells however did not change secretion from placental explants.While all statins up-regulated heme-oxygenase 1 in endothelial cells, only simvastatin up-regulated its expression in placenta from patients with preterm preeclampsia.ConclusionSimvastatin may be a more potent inhibitor of sFlt-1 secretion from endothelial cells, trophoblast cells and placenta from women with preterm preeclampsia than either pravastatin or rosuvastatin.
Highlights
Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 [1] and soluble endoglin [2] into the maternal circulation leading to hypertension, proteinuria and multi-system organ injury [3,4,5,6,7]
Statin treatment of endothelial cells, primary trophoblasts and placental explants obtained from patients with preterm preeclampsia We have previously reported the effect of pravastatin on endothelial cells, primary trophoblasts and preeclamptic placental explants [10]
We dose matched pravastatin to simvastatin and rosuvastatin and included a dose that has an effect on soluble fms-like tyrosine kinase 1 (sFlt-1), in order to perform a comparison of potency
Summary
Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) These anti-angiogenic factors cause hypertension and multi-organ injury. Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) [1] and soluble endoglin (sENG) [2] into the maternal circulation leading to hypertension, proteinuria and multi-system organ injury [3,4,5,6,7]. Others have shown pravastatin [10] and simvastatin [9] reduce sFlt-1 secretion from human placental tissue This is a desirable feature of a preeclampsia therapeutic as sFlt-1 is a likely pathogenic protein of the disease [1]. When sFlt-1 levels were reduced in preeclamptic patients by plasma apheresis, there was a possible stabilisation of disease [16]
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