LncRNA IGF2-AS Regulates Nucleotide Metabolism by Mediating HMGA1 to Promote Pyroptosis of Endothelial Progenitor Cells in Sepsis Patients.

Guibin Liang,Xin Jin,Zhihui He,Menghao Zeng,Wei Xing,Hao Ou,Min Gao,Longtian Deng,Qianlu Wang,Nattaya Konsue

doi:10.1155/2022/9369035

Guibin Liang, Xin Jin + Show 8 more

Open Access

https://doi.org/10.1155/2022/9369035

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Abstract

Background Sepsis is one of the major causes of death worldwide, and its high mortality and pathological complexity hinder early accurate diagnosis. We aimed to investigate lncRNA IGF2-AS and HMGA1 effects on pyroptosis of endothelial progenitor cells (EPCs) in sepsis patients and the mechanisms involved. Methods Blood samples from sepsis patients and healthy subjects were collected, and EPCs were isolated and identified. We constructed cell lines that knocked down lncRNA IGF2-AS, HMGA1, and TYMS. Furthermore, lncRNA IGF2-AS was overexpressed. Subsequently, dNTP treatment with different concentrations was performed to investigate lncRNA IGF2-AS and HMGA1 effects on pyroptosis of EPCs in sepsis patients. Finally, exosomes were isolated from bone marrow mesenchymal stem cells (MSCs) to detect lncRNA IGF2-AS expression, and the influence of MSC-derived exosomal lncRNA IGF2-AS on sepsis was preliminarily discussed. Results Compared with Healthy group, lncRNA IGF2-AS, HMGA1, and TYMS were highly expressed in Sepsis group. Compared with si-NC group, si-lncRNA IGF2-AS group had increased proliferation ability, decreased pyroptosis, decreased HMGA1, RRM2, TK1, and TYMS expressions. lncRNA IGF2-AS played a regulatory role by binding HMGA1. Compared with si-NC group, the proliferation ability of si-HMGA1 group increased, pyroptosis decreased, and RRM2, TK1, and TYMS expressions also decreased. Compared with si-NC group, pyroptosis in si-TYMS group was reduced. In addition, HMGA1 was related and bound to TYMS. After overexpressing lncRNA IGF2-AS, dNTP level decreased, while the proliferation increased and pyroptosis decreased with higher concentration of dNTP. In addition, we found that EPCs took up MSC-exosomes. Compared with supernatant group, lncRNA IGF2-AS was expressed in exosomes group. Compared with EPCs group, EPCs+exosomes group had increased lncRNA IGF2-AS expression and increased pyroptosis. Conclusions lncRNA IGF2-AS regulated nucleotide metabolism by mediating HMGA1 to promote pyroptosis of EPCs in sepsis patients. This study provided important clues for finding new therapeutic targets for sepsis.

Highlights

Sepsis is a life-threatening organ dysfunction caused by the host’s dysregulated response to infection [1]
IF staining Caspase-1 showed that after overexpression of Long noncoding RNAs (lncRNAs) IGF2-AS, the higher concentration of dNTP was given, the less positive Caspase-1 expression was, inhibiting pyroptosis (Figure 5(e)). These results indicated that overexpression of lncRNA IGF2-AS reduced the level of dNTP, while dNTPs could save the phenotype of lncRNA IGF2-AS
Compared with the endothelial progenitor cells (EPCs) group, the pyroptosis of the EPCs+exosomes group was increased, and the expressions of pyroptosis-related factors ASC, Caspase-1, NLRP3, and IL-18 were increased (Figures 6(g)–6(i)). These results revealed that MSCderived exosomal lncRNA IGF2-AS might promote pyroptosis of EPCs in sepsis patients

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by the host’s dysregulated response to infection [1] It is one of the major causes of death worldwide, and its high mortality and pathological complexity hinder early accurate diagnosis [2]. We aimed to investigate lncRNA IGF2-AS and HMGA1 effects on pyroptosis of endothelial progenitor cells (EPCs) in sepsis patients and the mechanisms involved. Compared with Healthy group, lncRNA IGF2-AS, HMGA1, and TYMS were highly expressed in Sepsis group. Compared with si-NC group, si-lncRNA IGF2-AS group had increased proliferation ability, decreased pyroptosis, decreased HMGA1, RRM2, TK1, and TYMS expressions. Compared with si-NC group, the proliferation ability of si-HMGA1 group increased, pyroptosis decreased, and RRM2, TK1, and TYMS expressions decreased. This study provided important clues for finding new therapeutic targets for sepsis

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