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联合使用二甲双胍和柳氮磺胺吡啶可显著减少胎盘分泌的抗血管生成因子:对子痫前期治疗的启示。

Combining metformin and sulfasalazine additively reduces the secretion of antiangiogenic factors from the placenta: Implications for the treatment of preeclampsia.

机构信息

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne. Mercy Perinatal, Mercy Hospital for Women, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne. Mercy Perinatal, Mercy Hospital for Women, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.

出版信息

Placenta. 2020 Jun;95:78-83. doi: 10.1016/j.placenta.2020.04.010. Epub 2020 Apr 25.

Abstract

INTRODUCTION

The antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are elevated in preeclampsia and have been implicated in its pathogenesis. We have previously demonstrated metformin and sulfasalazine independently reduce antiangiogenic factor secretion. Here we examined whether combining metformin and sulfasalazine may be more effective than either alone in reducing placental expression and secretion of antiangiogenic and angiogenic factors and the expression of markers of endothelial dysfunction.

METHODS

We performed functional experiments using primary human placenta to explore the effect of metformin and sulfasalazine, at lower doses than previously explored, individually and in combination, on sFlt-1 and sENG secretion and placental growth factor (PlGF) and vascular endothelial growth factor (VEGFα) expression. Using primary endothelial cells we induced dysfunction using cytokine tumor necrosis factor-α (TNF-α) and assessed the effect of low dose combination treatment on the expression of vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (a potent vasoconstrictor).

RESULTS

We demonstrated combination metformin and sulfasalazine was additive in reducing sFlt-1 secretion from cytotrophoblasts and placental explants. Combination treatment was also additive in reducing sENG secretion from placental explants. Furthermore, combination treatment increased cytotrophoblast VEGFα mRNA expression. Whilst combination treatment increased PlGF mRNA expression this was similar to treatment with sulfasalazine alone. Combination therapy reduced TNFα induced endothelin-1 mRNA expression however did not change VCAM expression.

DISCUSSION

Low dose combination metformin and sulfasalazine reduced cytotrophoblast sFlt-1 and sENG secretion, increased VEGFα expression and reduced TNFα induced endothelin-1 expression in primary endothelial cells. Combination therapy has potential to treat preeclampsia.

摘要

简介

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)在子痫前期升高,并与该病的发病机制有关。我们之前已经证明二甲双胍和柳氮磺胺吡啶可独立降低抗血管生成因子的分泌。在此,我们研究了二甲双胍和柳氮磺胺吡啶联合应用是否比单独应用更能有效降低胎盘抗血管生成和促血管生成因子的表达以及内皮功能障碍标志物的表达。

方法

我们使用原代人胎盘进行功能实验,研究了二甲双胍和柳氮磺胺吡啶(剂量低于之前研究的剂量)单独和联合应用对 sFlt-1 和 sENG 分泌以及胎盘生长因子(PlGF)和血管内皮生长因子(VEGFα)表达的影响。我们使用原代内皮细胞诱导细胞因子肿瘤坏死因子-α(TNF-α)引起功能障碍,并评估了低剂量联合治疗对血管细胞黏附分子-1(VCAM-1)和内皮素-1(一种强效血管收缩剂)表达的影响。

结果

我们证实,二甲双胍和柳氮磺胺吡啶联合应用可协同降低滋养细胞和胎盘组织匀浆中 sFlt-1 的分泌。联合治疗还可协同降低胎盘组织中 sENG 的分泌。此外,联合治疗可增加滋养细胞 VEGFαmRNA 的表达。虽然联合治疗可增加 PlGFmRNA 的表达,但与柳氮磺胺吡啶单独治疗相似。联合治疗可降低 TNF-α诱导的内皮素-1mRNA 的表达,但不改变 VCAM 的表达。

讨论

低剂量联合二甲双胍和柳氮磺胺吡啶可降低原代内皮细胞中滋养细胞的 sFlt-1 和 sENG 分泌,增加 VEGFα 的表达,并降低 TNF-α 诱导的内皮素-1 的表达。联合治疗可能对治疗子痫前期有一定作用。

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