A novel peptide relieves endothelial cell dysfunction in preeclampsia by regulating the PI3K/mTOR/HIF1α 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-α 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-α 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/HIF1α signaling pathway was activated by PDCC4, and a selective PI3K inhibitor reversed the protective function of PDCC4 on TNF-α 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/HIF1α signaling pathway and may be a potential therapy for PE.

A novel peptide promotes human trophoblast proliferation and migration through PI3K/Akt/mTOR signaling pathway

“…In this study, we identified that the expression of p-PI3K, p-AKT and p-mTOR were up-regulated following ROPPIP treatment, implying that the activation of the PI3K/AKT/mTOR signaling pathway may be correlated with the function of ROPPIP in promoting trophoblast proliferation and migration. Previous studies have revealed that PI3K inhibitor LY294002 was used to inhibit the proliferation and migration of damaged endothelial cells promoted by PDCC4 (Peptide derived from complement C4 A chain) in PE (38). Therefore, the PI3K inhibitor is possibly related to the biological functions of trophoblasts regulated by the ROPPIP/PI3K/AKT/mTOR pathway.SORL1 stimulates, via the N-terminal ectodomain, the proliferation and migration of smooth muscle cells, possibly by increasing cell surface expression of the urokinase receptor uPAR/ PLAUR (22).…”

The Novel Peptide AEDPPE Alleviates Trophoblast Cell Dysfunction Associated With Preeclampsia by Regulating the NF-κB Signaling Pathway

“…It has been found in numerous studies that LPS leads to the destruction of trophoblast function and activation of the NF-κB pathway in rats, thereby establishing a PE-like rat model (22,32,53), and we similarly generated a PE-like rat model by administering LPS to pregnant rats. Twenty-fourhour urinary protein of LPS-stimulated rats was significantly increased on the 7th day of pregnancy, as was systolic blood pressure after the 11th day.…”

“…Antimicrobial peptides (AMPs) from tilapia also manifest an antitumor effect by destroying the microtubular network in cells (21). In our previous study, we found that peptides derived from the serum of patients with PE significantly protected against endothelial dysfunction in umbilical vein vessels (22,23). Thus, the exploration of peptides with therapeutic properties for PE may provide novel candidates for the future treatment of PE.…”

The casein-derived peptide YFYPEL alleviates intestinal epithelial cell dysfunction associated with NEC by regulating the PI3K/AKT signaling pathway

“…FHC and IEC-6 cells were exposed to treatment with FITC-labeled peptide YFYPEL (10 μM) for 2 h, then fixed for 10 min with 4% paraformaldehyde, stained for 15 min with DAPI, and seen under a fluorescence microscope (Zeiss, Germany). 17 The F-actin was tested as previous study descrided 18 in FHC cells and seen under the confocal microscope (Zeiss, Germany).…”

“…Using a sterile pipet tip, a wound was generated inside the confluent monolayer by scraping a layer of confluent cells. 17 The peptide YFYPEL was introduced to serum-free culture media for 1 h prior to LPS (50 μg ml −1 ) exposure. Scratched areas were observed under a microscope (Zeiss, Germany).…”