Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model

Saif, Jaimy; Ahmad, Shakil; Rezai, Homira; Litvinova, Karina S.; Sparatore, Anna; Alzahrani, Faisal; Wang, Keqing; Ahmed, Asif

doi:10.1016/j.redox.2020.101814

Cited by 21 publications

(24 citation statements)

References 60 publications

(41 reference statements)

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“…The mechanistic studies that we present seem to demonstrate that the impact of environmental pollutants upon the health risk is genuine and that the generation of oxidative stress in the placenta is a sensible and truthful mediator of placental diseases. As such, in the STOX1 mouse model of preeclampsia, we have shown previously that oxidative/nitrosative stress is a major cause of the onset of the disease [ 153 , 154 ], corroborating the importance of this pathway in hypertensive disorders of pregnancy [ 155 , 156 ].…”

Section: Final Considerations and Conclusionmentioning

confidence: 53%

The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

2022

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Oxidative stress (OS) plays a pivotal role in placental development; however, abnormal loads in oxidative stress molecules may overwhelm the placental defense mechanisms and cause pathological situations. The environment in which the mother evolves triggers an exposure of the placental tissue to chemical, physical, and biological agents of OS, with potential pathological consequences. Here we shortly review the physiological and developmental functions of OS in the placenta, and present a series of environmental pollutants inducing placental oxidative stress, for which some insights regarding the underlying mechanisms have been proposed, leading to a recapitulation of the noxious effects of OS of environmental origin upon the human placenta.

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Section: Final Considerations and Conclusionmentioning

confidence: 53%

The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

2022

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“…In this case, sFLT-1 overexpression is commonly used for generating the animal model of PE, whereas inhibiting FLT-1 can prevent PE. 38 , 39 It has been shown that sFLT-1/PlGF ratio is valuable in predicting the occurrence of PE. 40 , 41 Particularly, determination of sFLT-1/PlGF ratio becomes a valuable auxiliary means for PE diagnosis in the medical insurance system of France; a low ratio is regarded as a highly negative predictive value of PE, and unnecessary hospitalization and premature delivery can be avoided.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

Yu¹,

Zhao²,

Sun³

et al. 2022

IJGM

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Objective Preeclampsia (PE) is a pregnancy-specific multisystem disease as well as an important cause of maternal and perinatal death. This study aimed to analyze the placental transcriptional data and clinical information of PE patients available in the published database and predict the target genes for prevention of PE. Methods The clinical information and corresponding RNA data of PE patients were downloaded from the GEO database. Cluster analysis was performed to examine the correlation between different genotyping genes and clinical manifestations. Then, bioinformatic approaches including GO, KEGG, WGCNA, and GSEA were employed to functionally characterize candidate target genes involved in pathogenesis of PE. Results Two PE datasets GSE60438 and GSE75010 were obtained and combined, thereby providing the data of 205 samples in total (100 non-PE and 105 PE samples). After eliminating the batch effect, we grouped and analyzed the integrated data, and further performed GSEA analysis. It was found that the genes in group 1 and group 2 were different from those in normal samples. Moreover, WGCNA analysis revealed that genes in group 1 were up-regulated in turquoise module, including SASH1 , PIK3CB and FLT-1 , while genes in group 2 were up-regulated in the blue and brown modules. We further conducted GO and KEGG pathway enrichment analyses and found that the differential genes in turquoise module were mainly involved in biological processes such as small molecular catabolic process, while being highly enriched in pathways, including MAPK signaling pathway and Rap1 signaling pathway. Conclusion FLT-1 was conventionally used to predict PE risk, and sFLT-1 could also be used as an indicator to evaluate PE treatment effect. As a candidate biomarker for predicting PE, SASH1 may participate in proliferation, migration, invasion and epithelial mesenchymal transformation of human trophoblast cells by regulating MAPK pathway and Rap1 signaling pathway, thus affecting the progression of PE. The mechanism allowing PIK3CB to regulate PE development was not clear, while the gene could be another candidate biomarker for PE risk prediction. This is an exploratory study and our findings were still required verification in further studies.

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“…Since the administration of exogenous sFlt-1/sEng leads to the development of a HELLP-like syndrome, other models such as the reduced utero-placental perfusion (RUPP) ( Li et al, 2012 ) could be more suitable to study the cerebrovascular complications of preeclampsia. The RUPP model increases sFlt-1/sEng levels ( Gilbert et al, 2007 , 2009 ; Sun et al, 2020 ; Saif et al, 2021 ) and the permeability of the BBB ( Warrington et al, 2014 ), but none of the presented evidence has proposed a mechanism by which these anti-angiogenic factors could be involved in the cerebrovascular complications elicited by this condition.…”

Section: Is the Endothelial Dysfunction At The Bbb In Preeclampsia A ...mentioning

confidence: 94%

How Soluble Fms-Like Tyrosine Kinase 1 Could Contribute to Blood-Brain Barrier Dysfunction in Preeclampsia?

2022

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Preeclampsia is a pregnancy-related syndrome that courses with severe cerebrovascular complications if not properly managed. Findings from pre-clinical and clinical studies have proposed that the imbalance between pro- and anti-angiogenic factors exhibited in preeclampsia is a major component of its pathophysiology. In this regard, measurement of circulating levels of soluble tyrosine kinase-1 similar to fms (sFlt-1), a decoy receptor for vascular endothelial growth factor (VEGF), is a moderately reliable biomarker for the diagnosis of preeclampsia. However, few studies have established a mechanistic approach to determine how the high levels of sFlt-1 are responsible for the endothelial dysfunction, and even less is known about its effects at the blood-brain barrier (BBB). Since the expression pattern of VEGF receptors type 1 and 2 in brain endothelial cells differs from the observed in peripheral endothelial cells, and components of the neurovascular unit of the BBB provide paracrine secretion of VEGF, this compartmentalization of VEGF signaling could help to see in a different viewpoint the role of sFlt-1 in the development of endothelial dysfunction. In this article, we provide a hypothesis of how sFlt-1 could eventually be a protective factor for brain endothelial cells of the BBB under preeclampsia.

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Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model

Cited by 21 publications

References 60 publications

The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

How Soluble Fms-Like Tyrosine Kinase 1 Could Contribute to Blood-Brain Barrier Dysfunction in Preeclampsia?

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