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. 2024 May 11;13(5):591.
doi: 10.3390/antiox13050591.

Oxidative Stress, Lipid Peroxidation and Ferroptosis Are Major Pathophysiological Signatures in the Placental Tissue of Women with Late-Onset Preeclampsia

Miguel A Ortega  1   2 , Luis M Garcia-Puente  1   2 , Oscar Fraile-Martinez  1   2 , Tatiana Pekarek  1   2 , Cielo García-Montero  1   2 , Julia Bujan  1   2 , Leonel Pekarek  1   2 , Silvestra Barrena-Blázquez  2   3   4 , Raquel Gragera  1 , Inmaculada C Rodríguez-Rojo  3   4 , Patrocinio Rodríguez-Benitez  5   6   7   8 , Laura López-González  2   9 , Raul Díaz-Pedrero  2   9 , Melchor Álvarez-Mon  1   2   10 , Natalio García-Honduvilla  1   2 , Juan A De León-Luis  5   6   7 , Coral Bravo  5   6   7 , Miguel A Saez  1   2   11
Affiliations

Oxidative Stress, Lipid Peroxidation and Ferroptosis Are Major Pathophysiological Signatures in the Placental Tissue of Women with Late-Onset Preeclampsia

Miguel A Ortega et al. Antioxidants (Basel). .

Abstract

Preeclampsia, a serious and potentially life-threatening medical complication occurring during pregnancy, is characterized by hypertension and often accompanied by proteinuria and multiorgan dysfunction. It is classified into two subtypes based on the timing of diagnosis: early-onset (EO-PE) and late-onset preeclampsia (LO-PE). Despite being less severe and exhibiting distinct pathophysiological characteristics, LO-PE is more prevalent than EO-PE, although both conditions have a significant impact on placental health. Previous research indicates that different pathophysiological events within the placenta may contribute to the development of preeclampsia across multiple pathways. In our experimental study, we investigated markers of oxidative stress, ferroptosis, and lipid peroxidation pathways in placental tissue samples obtained from women with LO-PE (n = 68) compared to healthy control pregnant women (HC, n = 43). Through a comprehensive analysis, we observed an upregulation of specific molecules associated with these pathways, including NADPH oxidase 1 (NOX-1), NADPH oxidase 2 (NOX-2), transferrin receptor protein 1 (TFRC), arachidonate 5-lipoxygenase (ALOX-5), acyl-CoA synthetase long-chain family member 4 (ACSL-4), glutathione peroxidase 4 (GPX4) and malondialdehyde (MDA) in women with LO-PE. Furthermore, increased ferric tissue deposition (Fe3+) was observed in placenta samples stained with Perls' Prussian blue. The assessment involved gene and protein expression analyses conducted through RT-qPCR experiments and immunohistochemistry assays. Our findings underscore the heightened activation of inflammatory pathways in LO-PE compared to HC, highlighting the pathological mechanisms underlying this pregnancy disorder.

Keywords: ferroptosis; lipid peroxidation; oxidative stress; placental; preeclampsia.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Comparative analysis of NOX1 gene expression in late-onset preeclampsia (LO-PE) versus healthy control (HC) pregnant women. Panel (A) presents the results of RT-qPCR measurements for NOX1 gene expression. Panel (B) displays the IRS-score of NOX1 expression within placental villi. Panel (C) showcases histological images depicting NOX1 protein expression in placental villi of women with LO-PE, while Panel (D) contrasts this expression with that of HC individuals. p-values of 0.001 (***).
Figure 2
Figure 2
Comparative analysis of NOX2 gene expression in late-onset preeclampsia (LO-PE) versus healthy control (HC) pregnant women. Panel (A) presents the results of RT-qPCR measurements for NOX2 gene expression. Panel (B) displays the IRS-score of NOX2 expression within placental villi. Panel (C) showcases histological images depicting NOX2 protein expression in placental villi of women with LO-PE, while Panel (D) contrasts this expression with that of HC individuals. p-values of 0.01 (**).
Figure 3
Figure 3
Histopathological examination (Panel (A))of iron deposits conducted using Perls’ Prussian Blue staining, depicting positive villi in women with LO-PE (Panel (B)) and healthy control pregnant women (HC) group (Panel (C)). Statistical analysis revealed significant differences (p < 0.001, ***). Arrow = Iron deposit.
Figure 4
Figure 4
Comparative analysis of TFRC gene expression in late-onset preeclampsia (LO-PE) versus healthy control (HC) pregnant women. Panel (A) presents the results of RT-qPCR measurements for TFRC gene expression. Panel (B) displays the IRS-score of TFRC expression within placental villi. Panel (C) showcases histological images depicting TFRC protein expression in placental villi of women with LO-PE, while Panel (D) contrasts this expression with that of HC individuals. p-values of 0.001 (***).
Figure 5
Figure 5
Comparative analysis of ACSL4 gene expression in late-onset preeclampsia (LO-PE) versus healthy control (HC) pregnant women. Panel (A) presents the results of RT-qPCR measurements for ACSL4 gene expression. Panel (B) displays the IRS-score of ACSL4 expression within placental villi. Panel (C) showcases histological images depicting ACSL4 protein expression in placental villi of women with LO-PE, while Panel (D) contrasts this expression with that of HC individuals. p-values of 0.001 (***).
Figure 6
Figure 6
Comparative analysis of ALOX5 gene expression in late-onset preeclampsia (LO-PE) versus healthy control (HC) pregnant women. Panel (A) presents the results of RT-qPCR measurements for ALOX5 gene expression. Panel (B) displays the IRS-score of ALOX5 expression within placental villi. Panel (C) showcases histological images depicting ALOX5 protein expression in placental villi of women with LO-PE, while Panel (D) contrasts this expression with that of HC individuals. p-values of 0.001 (***).
Figure 7
Figure 7
Comparative analysis of GPX4 gene expression in late-onset preeclampsia (LO-PE) versus healthy control (HC) pregnant women. Panel (A) presents the results of RT-qPCR measurements for GPX4 gene expression. Panel (B) displays the IRS score of GPX4 expression within placental villi. Panel (C) showcases histological images depicting GPX4 protein expression in placental villi of women with LO-PE, while Panel (D) contrasts this expression with that of HC individuals. p-values of 0.01 (**).
Figure 8
Figure 8
Malondialdehyde (MDA) levels in pmol/mg in the placental tissues of pregnant women with healthy control (HC) pregnant women and late-onset preeclampsia (LO-PE).
See this image and copyright information in PMC

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