Engineered miR-122 inhibitors enhance endothelial mitochondrial efficiency and improve vascular function

MicroRNA-122-5p (miR-122) is primarily expressed by the liver and is increasingly released into the bloodstream during obesity. It impacts the function of non-liver tissues, such as vascular endothelial cells, and increases the risk of diabetic vasculopathy. Using a novel gamma-peptide-nucleic acid-based miR-122 inhibitor (?P-122-I), we show that miR-122 regulates blood glucose level and endothelial function in high-fat diet-fed mice. Targeting ?P-122-I to endothelial cells retains its ability to improve vascular function but reduces metabolic benefits compared to the non-targeted version. Our results show that the endothelial cells take up miR-122 through a neuropilin-1-dependent mechanism. The aortic transcriptomics analysis implicates the role of miR-122 in mitochondrial function. The aortas of high-fat diet-fed mice receiving an inhibitor of miR-122 were more efficient in oxygen consumption despite a decline in the expression of mitochondrial electron transport chain complexes, especially complex I. Our in vitro data show that miR-122 overexpression decreases the abundance of mitochondria with high membrane potential and spare respiratory capacity under hyperglycemic conditions. These findings support the therapeutic potential of the ?PNA-based miR-122 inhibition in diabetic vasculopathy. Overall design: 8-week-old mice (male) were fed a high-fat diet (HFD) for eight weeks. Two weeks after dietary intervention, these mice were intraperitoneally injected with either ?PSC, ?P-122-I, e-?P-SC, or e-?P-122-I (0.25 µmol.kg-1) for six weeks. The aorta was carefully isolated, cleaned, and RNA was isolated.