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Role of MiR-126a-3p in Endothelial Injury in Endotoxic Mice
Maoping Chu1, Shanshan Qin2, Rongzhou Wu1
1Children's Heart Center, the Second Affiliated Hospital & Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, China, 325027.
Objective:
Sepsis poses a serious global health problem with an overall mortality rate of 30%, in which the vascular injury is a major contributor. The study is to determine the expression profile of micro-RNAs in endotoxic vascular walls and their potential roles in sepsis-related vascular injury.
Design:
Prospective randomized study.
Setting:
Laboratory investigation.
Subjects:
Male C57BL/6 mice, average weight 26.5 ± 1.8 g.
Interventions:
Endotoxemia was induced in mice via lipopolysaccharide injection (20 mg/kg, intraperitoneal) (Sigma, St. Louis, MO). The control mice were injected with the same amount of saline (500 μL, intraperitoneal). In a subgroup of mice, a high dose of lipopolysaccharide (30 mg/kg, intraperitoneal) was applied to induce endotoxin-related death.
Measurements And Main Results:
The mi-RNA expression profiles in aortas from lipopolysaccharide-induced endotoxic mice were determined. The result demonstrated that some micro-RNAs were aberrantly expressed in endotoxic mouse arteries. Among them, the endothelial cell-enriched/endothelial cell-specific miR-126a-3p was significantly down-regulated in endotoxic mouse arteries, septic human vessels, as well as vascular endothelial cells isolated from endotoxic mice or treated with lipopolysaccharide. The down-regulation of miR-126a-3p occurred at transcriptional level via the decreased expression of Krüppel-like factor 2, which could be inhibited by Krüppel-like factor 2 over-expression via adenovirus expressing Krüppel-like factor 2. The down-regulation of miR-126a-3p in endothelial cells resulted in the increased apoptosis, and decreased proliferation and migration, which were inhibited by miR-126a-3p mimics. In vivo, over-expression of miR-126a-3p via lentivirus attenuated endotoxemia-induced injuries on endothelial function and vascular permeability. We found that SPRED1 and VCAM-1 were two direct target genes of miR-126a-3p related to miR-126a-3p-mediated effects in endotoxemia. Finally, the survival rate of endotoxic mice was significantly increased by the over-expression of miR-126a-3p.
Conclusions:
The results suggest that vascular micro-RNAs such as miR-126a-3p may represent novel mechanisms and new therapeutic targets for endotoxemia-induced vascular injury and endotoxic mortality.
Insights
Sepsis causes vascular injury, and this study found that miR-126a-3p is down-regulated in endotoxic conditions. Restoring miR-126a-3p levels improved vascular function and survival in mice, suggesting it as a therapeutic target.
Area of Science:
- Molecular Biology
- Vascular Biology
- Sepsis Research
Background:
- Sepsis is a major cause of mortality, with vascular injury being a key contributor.
- Understanding the molecular mechanisms of sepsis-induced vascular dysfunction is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the expression profile of microRNAs in endotoxic vascular walls.
- To determine the role of specific microRNAs, particularly miR-126a-3p, in sepsis-related vascular injury.
Main Methods:
- Lipopolysaccharide (LPS) was used to induce endotoxemia in a mouse model.
- MicroRNA expression profiling was performed on aortic tissues.
- In vitro and in vivo experiments were conducted to assess the functional impact of miR-126a-3p manipulation.
Main Results:
- Down-regulation of miR-126a-3p was observed in endotoxic mouse arteries and human septic vessels.
- miR-126a-3p down-regulation led to increased endothelial cell apoptosis and decreased proliferation/migration.
- Over-expression of miR-126a-3p attenuated endotoxemia-induced vascular injury and improved survival rates in mice.
Conclusions:
- Vascular microRNAs, such as miR-126a-3p, play a significant role in endotoxemia-induced vascular injury.
- miR-126a-3p represents a potential novel therapeutic target for sepsis-related vascular complications and mortality.
