Kaitu'u-Lino Tu'uhevaha J, Brownfoot Fiona C, Beard Sally, Cannon Ping, Hastie Roxanne, Nguyen Tuong V, Binder Natalie K, Tong Stephen, Hannan Natalie J
Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
PLoS One. 2018 Feb 21;13(2):e0188845. doi: 10.1371/journal.pone.0188845. eCollection 2018.
The discovery of new treatments that prevent or treat preeclampsia would be a major advance. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. We recently identified metformin and esomeprazole as potential treatments for preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction.
We set out to assess whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (verses drug alone). Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-α (TNF-α) was added to endothelial cells to induce dysfunction in vitro. We examined the ability of metformin + esomeprazole to rescue TNF-α induced vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (ET-1) expression, leukocyte adhesion (markers of endothelial dysfunction).
Combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-α-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-α induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression.
In conclusion combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction. The combination of metformin and esomeprazole may provide a more effective treatment or prevention for preeclampsia compared to either as single agents.
发现预防或治疗子痫前期的新疗法将是一项重大进展。抗血管生成因子可溶性fms样酪氨酸激酶-1（sFlt-1）和可溶性内皮糖蛋白（sENG）从胎盘过量分泌，导致高血压、内皮功能障碍和多器官损伤。我们最近确定二甲双胍和埃索美拉唑是子痫前期的潜在治疗方法。两者都可减少胎盘和内皮细胞分泌sFlt-1和可溶性内皮糖蛋白，并减轻内皮功能障碍。
我们着手评估二甲双胍和埃索美拉唑联合使用是否会额外降低sFlt-1和可溶性内皮糖蛋白的分泌，并减轻内皮功能障碍（与单独使用药物相比）。将二甲双胍和埃索美拉唑添加到原代胎盘细胞和组织以及内皮细胞中，并在体外评估它们对sFlt-1和可溶性内皮糖蛋白分泌的影响。向内皮细胞中添加肿瘤坏死因子-α（TNF-α）以在体外诱导功能障碍。我们研究了二甲二甲双胍+埃索美拉唑挽救TNF-α诱导的血管细胞黏附分子-1（VCAM-1）和内皮素-1（ET-1）表达、白细胞黏附（内皮功能障碍标志物）的能力。
二甲双胍和埃索美拉唑联合使用在减少原代细胞滋养层、胎盘外植体和内皮细胞中sFlt-1分泌以及sFlt-1 e15a mRNA亚型表达方面具有相加作用。相比之下，二甲双胍和埃索美拉唑联合使用未观察到sENG的额外减少。低剂量的二甲双胍+埃索美拉唑联合使用可额外降低TNF-α诱导的VCAM-1 mRNA，但不能降低VCAM-1蛋白表达。二甲双胍和埃索美拉唑联合使用对TNF-α诱导的PBMC黏附于内皮细胞没有额外的降低作用。然而，二甲双胍和埃索美拉唑联合使用可额外降低ET-1 mRNA表达。
总之，二甲双胍和埃索美拉唑联合使用可额外降低sFlt-1的分泌以及内皮功能障碍标志物。与单一药物相比，二甲双胍和埃索美拉唑联合使用可能为子痫前期提供更有效的治疗或预防方法。
