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Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
miR-145a Regulation of Pericyte Dysfunction in a Murine Model of Sepsis
Yan Wu1, Pengfei Li1, Andrew J Goodwin2
1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Background:
Sepsis is a life-threatening systemic disease with severe microvascular dysfunction. Pericytes preserve vascular homeostasis. To our knowledge, the potential roles of microRNAs in sepsis-induced pericyte dysfunction have not been explored.
Methods:
We determined lung pericyte expression of miR-145a in cecal ligation and puncture (CLP)-induced sepsis. Mouse lung pericytes were isolated and transfected with a miR-145a mimic, followed by stimulation with lipopolysaccharide (LPS). We measured inflammatory cytokine levels. To assess the functions of miR-145a in vivo, we generated a pericyte-specific miR-145a-knockout mouse and determined sepsis-induced organ injury, lung and renal vascular leakage, and mouse survival rates. We used RNA sequencing and Western blotting to analyze the signaling pathways regulated by miR-145a.
Results:
CLP led to decreased miR-145a expression in lung pericytes. The miR-145a mimic inhibited LPS-induced increases in cytokines. In CLP-induced sepsis, pericytes lacking miR-145a exhibited increased lung and kidney vascular leakage and reduced survival rates. We found that miR-145a could suppress LPS-induced NF-κB activation. In addition, we confirmed that the transcription factor Friend leukemia virus integration 1 (Fli-1) is a target of miR-145a and that Fli-1 activates NF-κB signaling.
Conclusion:
Our results demonstrated that pericyte miR-145a mediates sepsis-associated microvascular dysfunction, potentially by means of Fli-1-mediated modulation of NF-κB signaling.
Insights
MicroRNA-145a protects against sepsis-induced microvascular dysfunction by regulating NF-κB signaling. This finding offers a potential therapeutic target for sepsis treatment.
Area of Science:
- Vascular Biology
- Molecular Medicine
- Sepsis Pathophysiology
Background:
- Sepsis is a critical illness characterized by severe microvascular dysfunction.
- Pericytes are crucial for maintaining vascular homeostasis.
- The role of microRNAs in sepsis-related pericyte dysfunction remains largely unexplored.
Purpose of the Study:
- To investigate the expression and function of microRNA-145a (miR-145a) in sepsis-induced pericyte dysfunction.
- To elucidate the molecular mechanisms underlying miR-145a's role in sepsis-associated microvascular injury.
Main Methods:
- Determined lung pericyte miR-145a expression in a mouse model of sepsis (cecal ligation and puncture).
- Utilized miR-145a mimics and lipopolysaccharide (LPS) stimulation in vitro.
- Generated pericyte-specific miR-145a-knockout mice to assess in vivo functions.
- Analyzed signaling pathways using RNA sequencing and Western blotting.
Main Results:
- Cecal ligation and puncture sepsis decreased lung pericyte miR-145a expression.
- miR-145a mimic inhibited LPS-induced inflammatory cytokine production.
- Pericytes lacking miR-145a showed increased vascular leakage and reduced survival rates in sepsis.
- miR-145a suppressed NF-κB activation, targeting the transcription factor Fli-1.
Conclusions:
- Pericyte miR-145a plays a critical role in mediating sepsis-associated microvascular dysfunction.
- miR-145a exerts its protective effects by modulating the Fli-1/NF-κB signaling pathway.
- Targeting pericyte miR-145a represents a potential therapeutic strategy for sepsis.
