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A novel peptide relieves endothelial cell dysfunction in preeclampsia by regulating the PI3K/mTOR/HIF1? pathway.

ABSTRACT: Preeclampsia (PE) is a pregnancy?specific complication characterized by hypertension and proteinuria, and it is one of the primary global causes of maternal and perinatal mortality. Poor remodeling of placental arteries and endothelial dysfunction serve important roles in the pathogenesis of PE. Peptide derived from complement C4 A chain (PDCC4) was identified in our previous peptidome analysis of serum from patients with PE. The present study aimed to investigate the effect of PDCC4 on endothelial dysfunction in PE. TNF?? stimulated HUVECs were employed to mimic endothelial dysfunction in PE, and Cell Counting Kit 8 assay, wound healing assay, tube formation assay, RNA?sequencing (seq) and western blot analysis were performed using HUVECs. Moreover, an in vivo model of PE was established using pregnant rats treated with lipopolysaccharide (LPS), and blood pressure monitoring, histopathological examination, ELISA and immunohistochemistry were performed on rats. It was found that TNF?? impaired proliferation, migration and tube formation of HUVECs, but pretreatment with PDCC4 moderated these effects. RNA?seq and western blotting demonstrated that the PI3K/mTOR/HIF1? signaling pathway was activated by PDCC4, and a selective PI3K inhibitor reversed the protective function of PDCC4 on TNF?? stimulated HUVECs. Additionally, PDCC4 alleviated hypertension, histopathological changes of placenta and kidney and the expression levels of endothelial injury markers and inflammatory cytokines induced by LPS in rats. These results suggested that PDCC4 relieved endothelial dysfunction in PE via PI3K/mTOR/HIF1? signaling pathway and may be a potential therapy for PE.

SUBMITTER: Xue L

PROVIDER: S-EPMC7723499 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A novel peptide relieves endothelial cell dysfunction in preeclampsia by regulating the PI3K/mTOR/HIF1α pathway.

Xue Lu L Xie Kaipeng K Wu Lan L Yu Xiang X Long Wei W Li Chanjuan C Jia Ruizhe R Ding Hongjuan H

International journal of molecular medicine 20201119 1

Preeclampsia (PE) is a pregnancy‑specific complication characterized by hypertension and proteinuria, and it is one of the primary global causes of maternal and perinatal mortality. Poor remodeling of placental arteries and endothelial dysfunction serve important roles in the pathogenesis of PE. Peptide derived from complement C4 A chain (PDCC4) was identified in our previous peptidome analysis of serum from patients with PE. The present study aimed to investigate the effect of PDCC4 on endothel ...[more]

PMID: 33236147

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Project description:BackgroundPreeclampsia (PE) is a complex pregnancy-related disease that endangers the safety of maternal and fetal. The purpose of this study is to reveal the pathogenesis of preeclampsia and discover new predictors from the perspective of peptidomics. The umbilical cord blood of PE and control group was analyzed by peptidomics. A peptide named Regulation of Proliferation Process in Preeclampsia (ROPPIP) was screened out to explore its role in the proliferation, migration and apoptosis of trophoblast cells in preeclampsia.MethodsWe compared and analyzed the umbilical cord blood of patients with PE and normal pregnant women using liquid chromatography-tandem mass spectrometry (LC-MS). hTR-8/Svneo cells cultured in vitro were divided into ROPPIP group and a disordered peptide group as control. Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Transwell chamber assays and western blot analysis were performed to detect cell proliferation, invasion, migration and apoptosis, in addition to the expression of Matrix metalloproteinase-2 (MMP2), nuclear associated antigen Ki67, B-cell lymphoma-2 (Bcl2), Caspase 3, and β-actin protein.ResultsWe identified 133 differential peptides. Of these, 51 were up-regulated while 82 were down-regulated. the polypeptide SFGVRMATASPTDGNV with low differential expression in the serum of PE patients was selected for the study, we named the polypeptide as Regulation of Proliferation Process in PE (ROPPIP). The experiment shows that ROPPIP can up-regulate the expression levels of MMP2, Ki67, and Bcl2 in HTR-8/Svneo cells, down-regulate the expression of caspase-3, promote the proliferation and migration of HTR-8/Svneo cells and inhibit the apoptosis induced by cisplatin, the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway may be associated with the function of ROPPIP.ConclusionsROPPIP promotes HTR-8/Svneo cells migration and proliferation, and inhibits apoptosis, by regulating the activation of the PI3K/AKT/mTOR signaling pathway.

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A novel peptide relieves endothelial cell dysfunction in preeclampsia by regulating the PI3K/mTOR/HIF1? pathway.

Publications

A novel peptide relieves endothelial cell dysfunction in preeclampsia by regulating the PI3K/mTOR/HIF1α pathway.

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