In vivo inhibition of miR-125b-5p modulates monocyte trafficking through the CCR7 receptor and reduces atherosclerosis

Background: Monocytes and regulatory non-coding RNAs play a crucial role in the development of atherosclerosis (ATH). We have previously shown that miR-125b-5p was upregulated in aortic macrophages and the aim of this paper was to further study the “in vivo” impact of miR-125b-5p in ATH progression. Methods: Eight-weeks-old ApoE -/- mice, fed with a high-fat diet for 14 weeks, were treated with a miR-125b-5p mimic, with its specific antagonist (antagomiR-125b), with a control scrambled sequence (control oligonucleotide SC) or with a control vehicle with phosphate-buffered saline (PBS) for 4 weeks. Results: Treatment with the miR-125b-5p mimic increased plaque sizes, macrophage infiltration, and NF-κB activation compared to PBS control, independently of cholesterol levels. In contrast, treatment with a specific antagomir produced opposite effects and increased the number of M2 macrophages. Lastly, the miR-125b-5p mimic was found to reduce expression of the chemokine receptor CCR7 in THP-1 cells, in RAW264.7 cells, as well as in the aortas and livers of mice, while the antagomiR-125b increased CCR7 expression. Reduced CCR7 expression was also observed in the aorta of patients with coronary artery disease. Conclusions: MiR-125b-5p mimic increased inflammation and ATH progression. Targeting miR-125b-5p with a specific antagomir reduced plaque size and macrophage infiltration and increased expression of the chemokine receptor CCR7. These results support a role for miR-125b-5p in the upregulation of CCR7 expression and monocyte trafficking, thus restricting vascular inflammation in ATH progression.