Involvement of the Heme Oxygenase System in the Development of Preeclampsia and as a Possible Therapeutic Target

Venditti, Carolina; Smith, Graeme N.

doi:10.2217/whe.14.54

Cited by 16 publications

(3 citation statements)

References 214 publications

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“…HO-1 is a cytoprotective enzyme with antioxidant activity that protects against ferroptosis [ 52 ]. A similar decrease in HO-1 activity was observed in PE [ 53 ], which was negatively correlated with Panx1 mRNA expression in this study. Taken together, our findings suggest that Panx1/HO-1 signaling contributes to ferroptosis in PE.…”

Section: Discussionsupporting

confidence: 90%

Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers

El-Khalik

Ibrahim

Ghafar

et al. 2022

J Assist Reprod Genet

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Purpose Ferroptosis is associated with oxidative stress (OS) and is caused by iron-dependent lipid-peroxidative damage, but its role in PE is unclear. The aim of this study is to determine whether pannexin 1 (Panx1) and toll-like receptor 4 (TLR4) are key regulators of ferroptosis in PE. Methods The study included 65 patients with PE and 25 healthy pregnant women. In normal and PE placental tissues, OS and ferroptosis markers, including Fe2+, malondialdehyde (MDA), reduced glutathione (GSH) levels, heme oxygenase-1 (HO-1) and glutathione peroxidase 4 (Gpx4) activity, were estimated. Panx1 and solute carrier family 7 member 11 (SLC7A11) mRNA expression levels were relatively quantified in placental tissues using real‐time polymerase chain reaction (RT‐PCR), while serum Panx1, serum TLR4, and placental activating transcription factor 3 (ATF3) levels were measured by ELISA. Results In placental tissues, Panx1 and TLR4 expression levels were significantly increased in patients with PE compared to controls and were positively correlated with pro-ferroptosis mediators such as placental Fe2+ and MDA levels and negatively correlated with anti-ferroptosis regulators such as placental GSH level, HO-1, and Gpx4 activity. Additionally, Panx1 and TLR4 had a positive correlation with ATF3 and a negative correlation with SLC7A11. Serum Panx1 and TLR4 levels were positively correlated with their placental tissue expression and showed good diagnostic capabilities for ferroptosis in PE. Conclusion Therefore, Panx1 and TLR4 are suggested to induce ferroptosis in PE via SLC7A11-mediated signaling pathways, offering a novel perspective on PE pathogenesis and novel diagnostic tools for PE.

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Section: Discussionsupporting

confidence: 90%

Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers

El-Khalik

Ibrahim

Ghafar

et al. 2022

J Assist Reprod Genet

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“…Indeed, the enzyme HO-1 is an important regulatory molecule present in most mammalian cells. In fact, the main function of HO-1 is to break down the pro-oxidant molecule heme into three products; carbon monoxide (CO), biliverdin and free iron and actively participate in the antioxidant defence in the human/animal body [ 240 ]. Indeed, HO-1 is a stress-inducible protein and can be induced by various oxidative and inflammatory signals.…”

Section: Effect Of Sm On Vitagene Expressionmentioning

confidence: 99%

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

2015

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Silymarin (SM), an extract from the Silybum marianum (milk thistle) plant containing various flavonolignans (with silybin being the major one), has received a tremendous amount of attention over the last decade as a herbal remedy for liver treatment. In many cases, the antioxidant properties of SM are considered to be responsible for its protective actions. Possible antioxidant mechanisms of SM are evaluated in this review. (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut. (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance. (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation is probably the main driving force of antioxidant (AO) action of SM. (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases. (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins and providing additional protection in stress conditions deserves more attention. (6) Affecting the microenvironment of the gut, including SM-bacteria interactions, awaits future investigations. (7) In animal nutrition and disease prevention strategy, SM alone, or in combination with other hepatho-active compounds (carnitine, betaine, vitamin B12, etc.), might have similar hepatoprotective effects as described in human nutrition.

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“…Smoking cigarettes has been shown to reduce the risk of developing PE by as much as 33% [5]. This risk reduction is not observed in smokeless tobacco users (snuff), suggesting that a combustible byproduct of cigarette smoke is responsible for this effect [6].…”

Section: Introductionmentioning

confidence: 99%

Carbon monoxide increases utero-placental angiogenesis without impacting pregnancy specific adaptations in mice

Dickson

Peterson

McRae

et al. 2020

Reprod Biol Endocrinol

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Background Cigarette smokers have a reduced risk of developing preeclampsia, possibly attributed to an increase in carbon monoxide (CO) levels. Carbon monoxide is a gasotransmitter that has been implicated in maintaining vascular tone, increasing angiogenesis, and reducing inflammation and apoptosis at physiological concentrations. Moderately increasing CO concentrations may have therapeutic potential to prevent or treat preeclampsia; however, the effects of CO on pregnancy are under studied. Our objective was to investigate the effect of CO on major angiogenic and inflammatory markers in pregnancy, and to evaluate the effect of CO on indicators of placental health. Findings Pregnant CD-1 mice were constantly exposed to either ambient air or 250 ppm CO from conception until gestation day (GD)10.5 or GD16.5. Using a qRT-PCR array, we identified that CO increased expression of major angiogenic genes at the implantation site on GD10.5, but not GD16.5. Pro-inflammatory cytokines in the plasma and tissue lysates from implantation sites in treated mice were not significantly different compared to controls. Additionally, CO did not alter the implantation site phenotype, in terms of proliferative capacity, invasiveness of trophoblasts, or abundance of uterine natural killer cells. Conclusions This study suggests that CO exposure is pro-angiogenic at the maternal-fetal interface, and is not associated with demonstrable concerns during murine pregnancy. Future studies are required to validate safety and efficacy of CO as a potential therapeutic for vascular insufficiency diseases such as preeclampsia and intrauterine growth restriction.

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Involvement of the Heme Oxygenase System in the Development of Preeclampsia and as a Possible Therapeutic Target

Cited by 16 publications

References 214 publications

Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers

Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

Carbon monoxide increases utero-placental angiogenesis without impacting pregnancy specific adaptations in mice

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