miRNA-149-5p protects endothelial function and attenuates sepsis-induced acute lung injury by targeting ABCA1
Wei Zhang1, Luofeng Jiang1, Xirui Tong1
1Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
Background:
Sepsis-induced acute lung injury (ALI) remains a leading cause of mortality in critically ill patients, characterized by endothelial barrier dysfunction and uncontrolled inflammation. While microRNAs regulate endothelial responses during sepsis, the role of miR-149-5p remains unclear.
Methods:
We conducted RNA-seq analysis to screen miR-149-5p expression in lipopolysaccharide (LPS)-stimulated endothelial cells, followed by functional validation via in vitro modulation of miR-149-5p with assessment of junction proteins (ZO-1, occludin, VE-cadherin) and adhesion molecules (ICAM1), as well as in vivo studies using a cecal ligation and puncture (CLP) mouse model treated with agomiR-149-5p. Mechanistic studies included bioinformatics predictions, dual-luciferase reporter assays to verify targets, and ABCA1 knockdown/overexpression rescue experiments.
Results:
Our findings revealed significant downregulation of miR-149-5p in LPS-stimulated endothelial cells. Restoring miR-149-5p expression upregulated tight/adherens junction proteins (ZO-1, occludin, VE-cadherin) and suppressed ICAM1 expression. In CLP mice, agomiR-149-5p attenuated lung injury by reducing alveolar edema, protein leakage, and immune cell infiltration, and by improving endothelial barrier function. Mechanistically, dual-luciferase assays confirmed direct binding of miR-149-5p to the ABCA1. ABCA1 knockdown mimicked the protective effects of miR-149-5p, while its overexpression exacerbated barrier dysfunction; furthermore, ABCA1 restoration abolished miR-149-5p-mediated protection.
Conclusions:
The miR-149-5p/ABCA1 axis represents a novel regulatory mechanism of endothelial homeostasis in sepsis-induced ALI. AgomiR-149-5p delivery demonstrates therapeutic potential by restoring barrier integrity and suppressing inflammation, offering a targeted strategy for critical care management.
Insights
MicroRNA-149-5p (miR-149-5p) protects against sepsis-induced acute lung injury by restoring endothelial barrier function. Therapeutic delivery of agomiR-149-5p shows promise for treating this critical condition.
Area of Science:
- Molecular Biology
- Cell Biology
- Critical Care Medicine
Background:
- Sepsis-induced acute lung injury (ALI) is a major cause of death in critically ill patients.
- Endothelial barrier dysfunction and inflammation characterize sepsis-induced ALI.
- The role of microRNA-149-5p (miR-149-5p) in sepsis-induced ALI is not well understood.
Purpose of the Study:
- To investigate the role of miR-149-5p in sepsis-induced ALI.
- To explore the therapeutic potential of modulating miR-149-5p in ALI.
Main Methods:
- RNA sequencing to screen miR-149-5p expression in lipopolysaccharide (LPS)-stimulated endothelial cells.
- In vitro and in vivo studies using agomiR-149-5p to modulate miR-149-5p levels in a mouse model of sepsis.
- Mechanistic studies including bioinformatics, dual-luciferase reporter assays, and ABCA1 manipulation.
Main Results:
- miR-149-5p was significantly downregulated in LPS-stimulated endothelial cells.
- Restoring miR-149-5p upregulated junction proteins and suppressed adhesion molecules, improving endothelial barrier function.
- AgomiR-149-5p treatment attenuated lung injury in mice by reducing edema, inflammation, and improving barrier function.
- miR-149-5p directly targets ABCA1, and this interaction is crucial for its protective effects.
Conclusions:
- The miR-149-5p/ABCA1 axis is a novel regulator of endothelial homeostasis in sepsis-induced ALI.
- AgomiR-149-5p demonstrates therapeutic potential for restoring barrier integrity and reducing inflammation in sepsis-induced ALI.
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