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Mitochondrial-targeted antioxidant attenuates preeclampsia-like phenotypes induced by syncytiotrophoblast-specific Gαq signaling.

ABSTRACT: Syncytiotrophoblast stress is theorized to drive development of preeclampsia, but its molecular causes and consequences remain largely undefined. Multiple hormones implicated in preeclampsia signal via the Gαq cascade, leading to the hypothesis that excess Gαq signaling within the syncytiotrophoblast may contribute. First, we present data supporting increased Gαq signaling and antioxidant responses within villous and syncytiotrophoblast samples of human preeclamptic placenta. Second, Gαq was activated in mouse placenta using Cre-lox and DREADD methodologies. Syncytiotrophoblast-restricted Gαq activation caused hypertension, kidney damage, proteinuria, elevated circulating proinflammatory factors, decreased placental vascularization, diminished spiral artery diameter, and augmented responses to mitochondrial-derived superoxide. Administration of the mitochondrial-targeted antioxidant Mitoquinone attenuated maternal proteinuria, lowered circulating inflammatory and anti-angiogenic mediators, and maintained placental vascularization. These data demonstrate a causal relationship between syncytiotrophoblast stress and the development of preeclampsia and identify elevated Gαq signaling and mitochondrial reactive oxygen species as a cause of this stress.

SUBMITTER: Opichka MA

PROVIDER: S-EPMC10691776 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Mitochondrial-targeted antioxidant attenuates preeclampsia-like phenotypes induced by syncytiotrophoblast-specific Gαq signaling.

Opichka Megan A MA Livergood M Christine MC Balapattabi Kirthikaa K Ritter McKenzie L ML Brozoski Daniel T DT Wackman Kelsey K KK Lu Ko-Ting KT Kozak Kaleigh N KN Wells Clive C Fogo Agnes B AB Gibson-Corley Katherine N KN Kwitek Anne E AE Sigmund Curt D CD McIntosh Jennifer J JJ Grobe Justin L JL

Science advances 20231201 48

Syncytiotrophoblast stress is theorized to drive development of preeclampsia, but its molecular causes and consequences remain largely undefined. Multiple hormones implicated in preeclampsia signal via the Gαq cascade, leading to the hypothesis that excess Gαq signaling within the syncytiotrophoblast may contribute. First, we present data supporting increased Gαq signaling and antioxidant responses within villous and syncytiotrophoblast samples of human preeclamptic placenta. Second, Gαq was act ...[more]

PMID: 38039359

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Project description:Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus. There is a need for improved biomarkers for diagnosis and monitoring of this condition. Placental syncytiotrophoblasts at the maternal-fetal interface release nanoparticles, including extracellular microvesicles, into the maternal blood during pregnancy. Syncytiotrophoblast extracellular microvesicles (STEVs) are being studied for their diagnostic potential and for their potential physiologic role in preeclampsia. We hypothesized that STEV profiles in maternal circulation would be altered under conditions of preeclampsia compared to normal pregnancy. Extracellular vesicles (EVs) released by BeWo cells in vitro showed high expression of syncytin-1, but no plac1 expression, demonstrating that trophoblast cell EVs express syncytin-1 on their surface. Placental alkaline phosphatase also showed high expression on BeWo EVs, but due to concern for cross reactivity to highly prevalent isoforms of intestinal and bone alkaline phosphatase, we utilized syncytin-1 as a marker for STEVs. In vivo, syncytin-1 protein expression was confirmed in maternal plasma EVs from Control and Preeclampsia subjects by Western blot, and overall, lower expression was noted in samples from patients with preeclampsia (n?=?8). By nanoparticle analysis, EV profiles from Control and Preeclampsia groups showed similar total plasma EV quantities (p?=?0.313) and size distribution (p?=?0.415), but STEV quantitative signal, marked by syncytin-1 specific EVs, was significantly decreased in the Preeclampsia group (p?=?2.8 × 10-11). Receiver operating characteristic curve demonstrated that STEV signal threshold cut-off of <0.316 was 95.2% sensitive and 95.6% specific for diagnosis of preeclampsia in this cohort (area under curve = 0.975 ± 0.020). In conclusion, we report that the syncytin-1 expressing EV profiles in maternal plasma might serve as a placental tissue specific biomarker for preeclampsia.

Project description:Preeclampsia (PE), defined as new-onset hypertension and multi-organ systemic complication during pregnancy, is the leading cause of maternal and neonatal mortality and morbidity. With extracellular vesicles research progresses, current data refers to the possibility that ferroptosis may play a role in exosomal effects. Evidence has suggested that ferroptosis may contribute to the pathogenesis of preeclampsia by bioinformatics analyses. The purpose of the current study is to identify the potential ferroptosis-related genes in syncytiotrophoblast-derived extracellular vesicles (STB-EVs) of preeclampsia using bioinformatics analyses. Clinical characteristics and gene expression data of all samples were obtained from the NCBI GEO database. The differentially expressed mRNAs (DE-mRNAs) in STB-EVs of preeclampsia were screened and then were intersected with ferroptosis genes. Functional and pathway enrichment analyses of ferroptosis-related DE-mRNAs in STB-EVs were performed. Ferroptosis-related hub genes in STB-EVs were identified by Cytoscape plugin CytoHubba with a Degree algorithm using a protein-protein interaction network built constructed from the STRING database. The predictive performance of ferroptosis-related hub genes was determined by a univariate analysis of receiver operating characteristic (ROC). The miRNA-hub gene regulatory network was constructed using the miRwalk database. A total of 1976 DE-mRNAs in STB-EVs were identified and the most enriched item identified by gene set enrichment analysis was signaling by G Protein-Coupled Receptors (normalized enrichment score = 1.238). These DE-mRNAs obtained 26 ferroptosis-related DE-mRNAs. Ferroptosis-related DE-mRNAs of gene ontology terms and Encyclopedia of Genes and Genomes pathway enrichment analysis were enriched significantly in response to oxidative stress and ferroptosis. Five hub genes (ALB, NOX4, CDKN2A, TXNRD1, and CAV1) were found in the constructed protein-protein interaction network with ferroptosis-related DE-mRNAs and the areas under the ROC curves for ALB, NOX4, CDKN2A, TXNRD1, and CAV1 were 0.938 (CI: 0.815-1.000), 0.833 (CI: 0.612-1.000), 0.875 (CI: 0.704-1.000), 0.958 (CI: 0.862-1.000), and 0.854 (CI: 0.652-1.000) in univariate analysis of ROC. We constructed a regulatory network of miRNA-hub gene and the findings demonstrate that hsa-miR-26b-5p, hsa-miR-192-5p, hsa-miR-124-3p, hsa-miR-492, hsa-miR-34a-5p and hsa-miR-155-5p could regulate most hub genes. In this study, we identified several central genes closely related to ferroptosis in STB-EVs (ALB, NOX4, CDKN2A, TXNRD1, and CAV1) that are potential biomarkers related to ferroptosis in preeclampsia. Our findings will provide evidence for the involvement of ferroptosis in preeclampsia and improve the understanding of ferroptosis-related molecular pathways in the pathogenesis of preeclampsia.

Project description:ObjectivesWe investigated the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy.BackgroundOxidative stress has been implicated in hypertensive cardiovascular diseases. Mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase have been proposed as primary sites of reactive oxygen species (ROS) generation.MethodsThe mitochondrial targeted antioxidant peptide SS-31 was used to determine the role of mitochondrial oxidative stress in angiotensin II (Ang)-induced cardiomyopathy as well as in Gαq overexpressing mice with heart failure.ResultsAng induces mitochondrial ROS in neonatal cardiomyocytes, which is prevented by SS-31, but not the nontargeted antioxidant N-acetyl cysteine (NAC). Continuous administration of Ang for 4 weeks in mice significantly increased both systolic and diastolic blood pressure, and this was not affected by SS-31 treatment. Ang was associated with up-regulation of NADPH oxidase 4 (NOX4) expression and increased cardiac mitochondrial protein oxidative damage, and induced the signaling for mitochondrial biogenesis. Reducing mitochondrial ROS by SS-31 substantially attenuated Ang-induced NOX4 up-regulation, mitochondrial oxidative damage, up-regulation of mitochondrial biogenesis, and phosphorylation of p38 mitogen-activated protein kinase and prevented apoptosis, concomitant with amelioration of Ang-induced cardiac hypertrophy, diastolic dysfunction, and fibrosis, despite the absence of blood pressure-lowering effect. The NAC did not show any beneficial effect. The SS-31 administration for 4 weeks also partially rescued the heart failure phenotype of Gαq overexpressing mice.ConclusionsMitochondrial targeted peptide SS-31 ameliorates cardiomyopathy resulting from prolonged Ang stimulation as well as Gαq overexpression, suggesting its potential clinical application for target organ protection in hypertensive cardiovascular diseases.

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Mitochondrial-targeted antioxidant attenuates preeclampsia-like phenotypes induced by syncytiotrophoblast-specific Gαq signaling.

Publications

Mitochondrial-targeted antioxidant attenuates preeclampsia-like phenotypes induced by syncytiotrophoblast-specific Gαq signaling.

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