Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.

Sun X, He S, Wara AKM, Icli B, Shvartz E, Tesmenitsky Y, Belkin N, Li D, Blackwell TS, Sukhova GK, Croce K, Feinberg MW
Circ Res. 2014 114 (1): 32-40

PMID: 24084690 · PMCID: PMC4051320 · DOI:10.1161/CIRCRESAHA.113.302089

RATIONALE - Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation.

OBJECTIVE - To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis.

METHODS AND RESULTS - MiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E-deficient mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease. Systemic delivery of miR-181b resulted in a 2.3-fold overexpression of miR-181b in the aortic intima of apolipoprotein E-deficient mice and suppressed NF-κB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E-deficient/NF-κB-luciferase transgenic mice. MiR-181b significantly inhibited atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4+ T cells in the vessel wall. Mechanistically, miR-181b inhibited the expression of the target gene importin-α3, an effect that reduced NF-κB nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-κB signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-κB nuclear translocation in leukocytes does not involve importin-α3, but rather importin-α5, which miR-181b does not target, highlighting that inhibition of NF-κB signaling in the endothelium is sufficient to mediate miR-181b's protective effects.

CONCLUSIONS - Systemic delivery of miR-181b inhibits the activation of NF-κB and atherosclerosis through cell-specific mechanisms in the vascular endothelium. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases such as atherosclerosis.

MeSH Terms (16)

Animals Aorta Apolipoproteins E Atherosclerosis CD4-Positive T-Lymphocytes Diet, High-Fat Humans Human Umbilical Vein Endothelial Cells Inflammation Karyopherins Macrophages Mice Mice, Inbred C57BL MicroRNAs NF-kappa B Tunica Intima

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