Brownfoot Fiona C, Tong Stephen, Hannan Natalie J, Hastie Roxanne, Cannon Ping, Kaitu'u-Lino Tu'uhevaha J
Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
BMC Pregnancy Childbirth. 2016 May 20;16:117. doi: 10.1186/s12884-016-0902-3.
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. 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.
We 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.
All 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.
Simvastatin 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.
子痫前期与胎盘释放可溶性fms样酪氨酸激酶1（sFlt-1）和可溶性内皮糖蛋白（sENG）有关。这些抗血管生成因子会导致高血压和多器官损伤。普伐他汀在体外可减少胎盘sFlt-1的分泌，目前正在临床试验中作为子痫前期的潜在治疗方法进行研究。然而，不同类别的他汀类药物可能在降低sFlt-1分泌方面更有效。我们比较了三代不同他汀类药物对人内皮细胞、滋养层细胞和胎盘外植体中sFlt-1和sENG分泌的相对效力。
我们使用原代人脐静脉内皮细胞、滋养层细胞和早产子痫前期胎盘外植体进行功能实验，以评估辛伐他汀、瑞舒伐他汀和普伐他汀对sFlt-1和sENG分泌的影响，并比较每种他汀类药物在降低这些因子方面的相对效力（半数抑制浓度）。此外，我们评估了每种他汀类药物对抗氧化和细胞保护酶血红素加氧酶1的影响。
所有他汀类药物均降低了内皮细胞、滋养层细胞和早产子痫前期胎盘外植体中sFlt-1的分泌。辛伐他汀是内皮细胞（半数抑制浓度3.2 μM）、滋养层细胞（半数抑制浓度61.4 μM）和胎盘外植体中sFlt-1分泌的最有效抑制剂。与普伐他汀或瑞舒伐他汀相比，辛伐他汀在内皮细胞中降低sFlt-1分泌的效力分别高28倍和3倍，在滋养层细胞中降低sFlt-1分泌的效力分别高85倍和33倍。所有他汀类药物均增加了内皮细胞中sENG的分泌，但未改变胎盘外植体中的分泌。虽然所有他汀类药物均上调了内皮细胞中血红素加氧酶1的表达，但只有辛伐他汀上调了早产子痫前期患者胎盘中该酶的表达。
与普伐他汀或瑞舒伐他汀相比，辛伐他汀可能是早产子痫前期女性内皮细胞、滋养层细胞和胎盘中sFlt-1分泌的更有效抑制剂。
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