Unraveling Ammonia-Induced Brain Endothelial Senescence: Role of miRNA-183-5p

Aims: Hyperammonemia, defined by elevated ammonia levels, may co-occur in various neurological disorders, but its effects on cerebrovascularity are not fully understood. This study aimed to investigate how hyperammonemia affects brain endothelial cells senescence and selected within in silico analysis micro RNA-183-5p in this process. Results: Reduction in cerebrovascular density in hyperammonemia-induced rats, similar to that seen in 12-month-old rats, using von Willebrand factor staining, was observed. MicroRNA (miRNA) profile analysis of the brain cortex and plasma identified miRNA-183-5p contributing to endothelial senescence. In vitro studies of ammonia-treated rat brain endothelial cell line 4 showed senescent features, including increased β-galactosidase activity, higher mRNA levels and fluorescence intensity of p16 and p21, and altered senescence-associated secretory phenotype. Additionally, the transfection of miRNA-183-5p mimic induced similar senescent characteristics in endothelial cells, whereas miRNA-183-5p mimic inhibition reversed some effects. Innovation: This study is the first to link hyperammonemia-induced cerebrovascular dysfunction with miRNA-183-5p, highlighting its role in promoting endothelial senescence. The findings suggest that miRNA-183-5p could be a target for therapeutic interventions, preventing ammonia-induced brain endothelial dysfunction. Conclusion: Hyperammonemia promotes brain endothelial cells senescence through miRNA-183-5p, reducing cerebrovascular density. This may contribute to cerebral dysfunction seen in hyperammonemia-associated neurological disorders. Targeting miRNA-183-5p could offer a novel therapeutic strategy to mitigate endothelial dysfunction and preserve brain health in hyperammonemia. Antioxid. Redox Signal. 43, 254-271.