Hydroxychloroquine reduces soluble Flt-1 secretion from human cytotrophoblast, but does not mitigate markers of endothelial dysfunction in vitro

Kadife, Elif; Hannan, Natalie J.; Harper, Alesia; Binder, Natalie; Beard, Sally; Brownfoot, Fiona

doi:10.1371/journal.pone.0271560

Cited by 5 publications

(8 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to TNF-α, data on IL-6 concentration in the maternal circulation are inconsistent. Various studies demonstrated increased ( Takacs et al, 2003 ; Xiao et al, 2012 ; Pinheiro et al, 2015 ; Li et al, 2016 ; Aggarwal et al, 2019 ; Ma et al, 2019 ; Valencia-Ortega et al, 2019 ; Gencheva et al, 2022 ; Kadife et al, 2022 ) rather than unchanged ( Borekci et al, 2007 ; Salazar Garcia et al, 2018 ) IL-6 concentration in maternal sera and plasma. Xiao et al found a connection between IL-6 and the severity of PE ( Xiao et al, 2012 ).…”

Section: Adaptive Immune System In Pe and Hcq Immunomodulatory Proper...mentioning

confidence: 99%

“…In the context of PE, HCQ has been shown to reduce PE serum-triggered production of ET-1 and NOX in HUVECs ( Rahman et al, 2016 ). However, conflicting results have been obtained on the same type of cells for TNF-α-triggered ET-1 secretion ( Rahman et al, 2016 ; Kadife et al, 2022 ).…”

Section: Vascularity In Pe and Hcqmentioning

confidence: 99%

“…It has been shown that HCQ induces a decline of VCAM-1 in endothelial cells ( Le et al, 2014 ; Li et al, 2018 ; Hu Y. et al, 2022 ; Kadife et al, 2022 ; Gajić et al, 2023 ). It has been suggested that this inhibition goes through the activation of ERK5 ( Le et al, 2014 ; Cheng et al, 2018 ).…”

Section: Vascularity In Pe and Hcqmentioning

confidence: 99%

See 2 more Smart Citations

Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine’s biological mechanisms

Gajić,

Schröder-Heurich,

Mayer-Pickel

2024

Front. Pharmacol.

View full text Add to dashboard Cite

Preeclampsia (PE) is a complex pregnancy-related disorder characterized by hypertension, followed by organ dysfunction and uteroplacental abnormalities. It remains a major cause of maternal and neonatal morbidity and mortality worldwide. Although the pathophysiology of PE has not been fully elucidated, a two-stage model has been proposed. In this model, a poorly perfused placenta releases various factors into the maternal circulation during the first stage, including pro-inflammatory cytokines, anti-angiogenic factors, and damage-associated molecular patterns into the maternal circulation. In the second stage, these factors lead to a systemic vascular dysfunction with consecutive clinical maternal and/or fetal manifestations. Despite advances in feto-maternal management, effective prophylactic and therapeutic options for PE are still lacking. Since termination of pregnancy is the only curative therapy, regardless of gestational age, new treatment/prophylactic options are urgently needed. Hydroxychloroquine (HCQ) is mainly used to treat malaria as well as certain autoimmune conditions such as systemic lupus and rheumatoid arthritis. The exact mechanism of action of HCQ is not fully understood, but several mechanisms of action have been proposed based on its pharmacological properties. Interestingly, many of them might counteract the proposed processes involved in the development of PE. Therefore, based on a literature review, we aimed to investigate the interrelated biological processes of HCQ and PE and to identify potential molecular targets in these processes.

show abstract

Section: Adaptive Immune System In Pe and Hcq Immunomodulatory Proper...mentioning

confidence: 99%

Section: Vascularity In Pe and Hcqmentioning

confidence: 99%

See 1 more Smart Citation

Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine’s biological mechanisms

Gajić,

Schröder-Heurich,

Mayer-Pickel

2024

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Ambarwati et al (2017) discovered that HUVECs cultures exposed to plasma from preeclamptic patients produced antiangiogenic factors such as sFlt-1 and sEng considerably more than HUVECs cultures exposed to plasma from normal pregnant women (p<0,05). Other in vitro research claimed that when compared to HUVECs exposed to plasma from normal pregnant women, sFlt-1 levels in HUVECs cultures exposed to preeclampsia plasma increased significantly, and the cell structure looked to be harmed (Ambarwati et al, 2017;Chielie et al, 2020;Christanto et al, 2021;Gunardi et al, 2016;Kadife et al, 2022;Sánchez-Aranguren et al, 2014;Yeni et al, 2020).…”

Section: Effect Of Soybean Ethanol Extract On Sfit-1 Levels In Huvecs...mentioning

confidence: 99%

“…In the second stage, increased oxidative stress causes an imbalance of angiogenic factors, namely increased sFlt-1. Increased production of sFlt-1 will inhibit the production of placental growth factor (PlGF), which will trigger an increase in vasoconstrictors, namely ET-1 and TxA2, a decrease in vasodilators, namely PGI2 and NO, resulting in endothelial dysfunction in the maternal vascular system and leading to clinical manifestations of preeclampsia (Bokslag et al, 2016;Ives et al, 2020;Kadife et al, 2022;Keman, 2014;Phipps et al, 2020;Rana et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Effect of Soybean Extract on sFlt-1 LEVELS in Huvecs Cultures Induced by Preeclampsia Plasma

Indriyani,

Mestika,

Nurseta

et al. 2023

Med.Lab.Tech.J.

View full text Add to dashboard Cite

Preeclampsia is a dangerous pregnancy issue that causes hypertension at ≥20 weeks of gestation. Oxidative stress is known to play a role in the pathophysiology of preeclampsia by raising the activity of soluble fms-like tyrosine kinase 1 (sFlt-1) and causing endothelial dysfunction. As a result, antioxidants are utilized as a therapy in preeclampsia to protect the body from the impacts of free radicals. This study aims to determine the effect of soybean extract on sFlt-1 levels in HUVECs cultures exposed to preeclamptic plasma. The benefit of this study is the consideration for clinicians to provide soybean ethanol extract supplements (Glycine max) to increase the potential of antihypertensive therapy. Human umbilical vein endothelial cell cultures (HUVECs) were used in the study, which was conducted in vitro. HUVECs cultures were exposed to preeclampsia plasma and subsequently treated for 24 hours with various dosages of soybean extract. The enzyme-linked immunosorbent assay (ELISA) measured the sFlt-1 levels in each observation group. The hypothesis was tested using One-Way ANOVA analysis with SPSS version 25 software. This study found a significant difference (p <0,05) between the mean value of the positive control group and the negative control group. A significant difference was also found (p <0,05) in the mean value of sFlt-1 between the positive control group and the treatment group that was given soybean extract at doses of 17,5 ppm. Soybean extract had a significant effect on decreasing sFlt-1 levels in HUVECs cultures exposed to preeclamptic plasma. Thus, soybeans isoflavones have the potential to treat preeclampsia by reducing anti-angiogenic factors.

show abstract

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

Schröder‐Heurich

Mercnik

et al. 2023

IJMS

View full text Add to dashboard Cite

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 vascular cell adhesion protein 1 (VCAM-1) 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 IL-8 and VCAM-1 mRNA and secretion of IL-8, while in EO-PE fpECAs, a higher (10µg/mL) HCQ concentration slightly reduced the gene expression of IL-8. 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.

show abstract

Hydroxychloroquine reduces soluble Flt-1 secretion from human cytotrophoblast, but does not mitigate markers of endothelial dysfunction in vitro

Cited by 5 publications

References 38 publications

Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine’s biological mechanisms

Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine’s biological mechanisms

Effect of Soybean Extract on sFlt-1 LEVELS in Huvecs Cultures Induced by Preeclampsia Plasma

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

Contact Info

Product

Resources

About