Sepsis plasma-derived exosomal miR-1-3p induces endothelial cell dysfunction by targeting SERP1.

Abstract

Acute lung injury (ALI) is the leading cause of death in sepsis patients. Exosomes participate in the occurrence and development of ALI by regulating endothelial cell inflammatory response, oxidative stress and apoptosis, causing serious pulmonary vascular leakage and interstitial edema. The current study investigated the effect of exosomal miRNAs on endothelial cells during sepsis. We found a significant increase in miR-1-3p expression in cecal ligation and puncture (CLP) rats exosomes sequencing and sepsis patients' exosomes, and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) in vitro. However, the specific biological function of miR-1-3p in ALI remains unknown. Therefore, mimics or inhibitors of miR-1-3p were transfected to modulate its expression in HUVECs. Cell proliferation, apoptosis, contraction, permeability, and membrane injury were examined via cell counting kit-8 (CCK-8), flow cytometry, phalloidin staining, Transwell assay, lactate dehydrogenase (LDH) activity, and Western blotting. The miR-1-3p target gene was predicted with miRNA-related databases and validated by luciferase reporter. Target gene expression was blocked by siRNA to explore the underlying mechanisms. The results illustrated increased miR-1-3p and decreased stress-associated endoplasmic reticulum protein 1 (SERP1) expression both in vivo and in vitro. SERP1 was a direct target gene of miR-1-3p. Up-regulated miR-1-3p inhibits cell proliferation, promotes apoptosis and cytoskeleton contraction, increases monolayer endothelial cell permeability and membrane injury by targeting SERP1, which leads to dysfunction of endothelial cells and weakens vascular barrier function involved in the development of ALI. MiR-1-3p and SERP1 may be promising therapeutic candidates for sepsis-induced lung injury.

• Authors: Min Gao, Tianyi Yu, Dan Liu, Yan Shi, Peilang Yang, Jie Zhang, Jizhuang Wang, Yan Liu, Xiong Zhang
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 135 Issue 2 Pg. 347-365 (01 29 2021) ISSN: 1470-8736 [Electronic] England
• PMID: 33416075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s).

Chemical References

• Lipopolysaccharides
• Membrane Proteins
• MicroRNAs
• RNA, Small Interfering
• SERP1 protein, human

Topics

• Adult
• Animals
• Cecum (surgery)
• Disease Models, Animal
• Exosomes (genetics)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Ligation (methods)
• Lipopolysaccharides
• Male
• Membrane Proteins (genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Middle Aged
• RNA, Small Interfering (genetics)
• Rats
• Sepsis (physiopathology)