Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, A-8036 Graz, Austria.
Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
Int J Mol Sci. 2023 Jun 30;24(13):10934. doi: 10.3390/ijms241310934.
Hydroxychloroquine (HCQ), an anti-malarial drug, is suggested as a promising candidate for the treatment of pregnancy-related disorders associated with endothelial activation, among which there is preeclampsia (PE). Arterial feto-placental endothelial cells (fpECAs) were isolated from control (CTR) and early-onset preeclamptic (EO-PE) placentas. The aim of this study was to test potential protective effects of HCQ in an in vitro model of endothelial activation as well as in cells isolated from EO-PE placentas. To mimic PE conditions, CTR fpECAs were exposed to a pro-inflammatory environment consisting of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β (furtherly referred as MIX) with or without varying concentrations of HCQ (1 µg/mL and 10 µg/mL). Their effect on wound healing and endothelial barrier integrity was analyzed. Variations in the expression of IL-8 and leukocyte adhesion molecules (LAM) on both mRNA and protein levels were determined between CTR and PE fpECAs in the presence or absence of HCQ. MIX decreased wound healing and stability of the endothelial barrier, but HCQ did not affect it. Significant differences between CTR and EO-PE fpECAs were observed in IL-8 mRNA, protein secretion, and ( mRNA expression levels. After challenging CTR fpECAs with MIX, upregulation of both mRNA and protein levels was observed in all molecules. Combined treatment of HCQ and MIX slightly lowered VCAM-1 total protein amount. In CTR fpECAs, treatment with low concentrations of HCQ alone (1 µg/mL) reduced basal levels of and mRNA and secretion of IL-8, while in EO-PE fpECAs, a higher (10µg/mL) HCQ concentration slightly reduced the gene expression of . Conclusion: These results provide additional support for the safety of HCQ, as it did not adversely affect endothelial functionality in control fpECAs at the tested concentration. Furthermore, the observed limited effects on IL-8 secretion in EO-PE fpECAs warrant further investigation, highlighting the need for clinical trials to assess the potential therapeutic effects of HCQ in preeclampsia. Conducting clinical trials would offer a more comprehensive understanding of HCQ's efficacy and safety, allowing us to explore its potential benefits and limitations in a real-world clinical setting.
羟氯喹 (HCQ) 是一种抗疟药物，被认为是治疗与血管内皮激活相关的妊娠相关疾病的有前途的候选药物，其中包括子痫前期 (PE)。从对照 (CTR) 和早发型子痫前期 (EO-PE) 胎盘分离动脉胎儿胎盘内皮细胞 (fpECAs)。本研究的目的是在体外内皮激活模型以及从 EO-PE 胎盘分离的细胞中测试 HCQ 的潜在保护作用。为了模拟 PE 条件，将 CTR fpECAs 暴露于由肿瘤坏死因子 α (TNF-α)、白细胞介素 (IL)-6 和白细胞介素 1β (进一步称为 MIX) 组成的促炎环境中，同时存在或不存在不同浓度的 HCQ (1µg/mL 和 10µg/mL)。分析了它们对伤口愈合和内皮屏障完整性的影响。在存在或不存在 HCQ 的情况下，在 CTR 和 PE fpECAs 之间确定了白细胞介素 8 (IL-8) 和白细胞粘附分子 (LAM) 的 mRNA 和蛋白质水平的表达变化。在 MIX 作用下，CTR 和 EO-PE fpECAs 之间的差异在 IL-8 mRNA、蛋白分泌和 (mRNA 表达水平上有明显差异。在用 MIX 刺激 CTR fpECAs 后，所有分子的 mRNA 和蛋白质水平均上调。HCQ 和 MIX 的联合治疗略微降低了 VCAM-1 总蛋白量。在 CTR fpECAs 中，单独使用低浓度 HCQ(1µg/mL)可降低基础水平的 和 mRNA 以及 IL-8 的分泌，而在 EO-PE fpECAs 中，较高浓度 (10µg/mL) 的 HCQ 略微降低了基因表达 。结论：这些结果为 HCQ 的安全性提供了额外的支持，因为在测试浓度下，它不会对对照 fpECAs 的内皮功能产生不利影响。此外，在 EO-PE fpECAs 中观察到的 IL-8 分泌的有限作用需要进一步研究，这突显了进行临床试验以评估 HCQ 在子痫前期中的潜在治疗效果的必要性。进行临床试验将更全面地了解 HCQ 的疗效和安全性，使我们能够在真实的临床环境中探索其潜在的益处和局限性。
