A novel miRNA mimic attenuates organ injury after hepatic ischemia/reperfusion
Timothy Borjas1, Asha Jacob, Molly Kobritz
1From the Departments of (T.B., A.J., M.K., V.P., G.F.C., M.A., P.W.) Surgery and Molecular Medicine (A.J., M.A., P.W.), Zucker School of Medicine at Hofstra/Northwell; and Center for Immunology and Inflammation (T.B., A.J., M.K., M.A., P.W.), The Feinstein Institutes for Medical Research, Manhasset, New York.
Introduction:
Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel mediator of inflammation and tissue injury. It has been shown that miRNA 130b-3p acts as an endogenous inhibitor of eCIRP. Because RNA mimics are unstable after in vivo administration, we have chemically engineered miRNA 130b-3p mimic (named PS-OMe miR130) to improve its stability by protection from nuclease activity. We hypothesize that PS-OMe miR130 reduces eCIRP-mediated injury and inflammation in a murine model of hepatic ischemia/reperfusion (I/R), a model of sterile inflammation.
Methods:
Adult male mice underwent 70% hepatic ischemia for 60 minutes and 24-hour reperfusion. At the start of reperfusion, mice were treated intravenously with vehicle (phosphate-buffered saline) or PS-OMe miR130. Blood and liver tissue were collected after 24 hours for biochemical analysis. Apoptosis in the liver tissue was determined by transferase dUTP nick-end labeling assay.
Results:
After hepatic I/R, organ injury markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly decreased after PS-OMe miR130 treatment. Furthermore, histological analysis of liver sections demonstrated significantly less injury in PS-OMe miR130 treatment mice versus vehicle mice. In addition, tumor necrosis factor α mRNA, interleukin-1β mRNA, and neutrophil infiltration (myeloperoxidase activity and granulocyte receptor 1 immunohistochemistry) were significantly attenuated after PS-OMe miR130 treatment. Finally, apoptosis significantly decreased in liver tissue after treatment.
Conclusion:
PS-OMe miR130 decreases eCIRP-mediated injury and inflammation in a murine model of hepatic I/R.
Insights
Chemically engineered miRNA 130b-3p mimic (PS-OMe miR130) effectively reduced inflammation and liver injury in a murine model of hepatic ischemia/reperfusion (I/R). This stable RNA mimic offers a promising therapeutic strategy for sterile inflammation.
Area of Science:
- Biomedical research
- Molecular biology
- Inflammation and immunology
Background:
- Extracellular cold-inducible RNA-binding protein (eCIRP) is a key mediator of inflammation and tissue damage.
- MicroRNA 130b-3p naturally inhibits eCIRP, but its in vivo instability limits therapeutic use.
- Chemical engineering created a stable miRNA 130b-3p mimic (PS-OMe miR130) for enhanced stability against nucleases.
Purpose of the Study:
- To investigate the efficacy of the stabilized miRNA 130b-3p mimic (PS-OMe miR130) in reducing eCIRP-mediated hepatic injury and inflammation.
- To evaluate PS-OMe miR130's therapeutic potential in a murine model of hepatic ischemia/reperfusion (I/R)-induced sterile inflammation.
Main Methods:
- Adult male mice underwent 70% hepatic ischemia for 60 minutes followed by 24-hour reperfusion.
- Mice received intravenous administration of either vehicle (phosphate-buffered saline) or PS-OMe miR130 at the start of reperfusion.
- Liver injury markers, histological damage, inflammatory markers (TNF-α, IL-1β), neutrophil infiltration, and apoptosis were assessed.
Main Results:
- PS-OMe miR130 treatment significantly decreased liver injury markers (AST, ALT, LDH) and histological damage post-hepatic I/R.
- Inflammatory markers (TNF-α, IL-1β mRNA) and neutrophil infiltration were significantly attenuated in the PS-OMe miR130 group.
- Apoptosis in liver tissue was significantly reduced following PS-OMe miR130 administration.
Conclusions:
- The stabilized miRNA 130b-3p mimic, PS-OMe miR130, effectively mitigates eCIRP-driven hepatic injury and inflammation.
- PS-OMe miR130 demonstrates therapeutic promise for managing sterile inflammation in hepatic I/R injury.
