| First Author | Sun X | Year | 2014 |
| Journal | Circ Res | Volume | 114 |
| Issue | 1 | Pages | 32-40 |
| PubMed ID | 24084690 | Mgi Jnum | J:221463 |
| Mgi Id | MGI:5639195 | Doi | 10.1161/CIRCRESAHA.113.302089 |
| Citation | Sun X, et al. (2014) Systemic delivery of microRNA-181b inhibits nuclear factor-kappaB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice. Circ Res 114(1):32-40 |
| abstractText | RATIONALE: Activated nuclear factor (NF)-kappaB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-kappaB may provide a novel strategy to limit chronic inflammation. OBJECTIVE: To examine the role of microRNA-181b (miR-181b) in endothelial NF-kappaB 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-kappaB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E-deficient/NF-kappaB-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-alpha3, an effect that reduced NF-kappaB nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-kappaB signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-kappaB nuclear translocation in leukocytes does not involve importin-alpha3, but rather importin-alpha5, which miR-181b does not target, highlighting that inhibition of NF-kappaB signaling in the endothelium is sufficient to mediate miR-181b's protective effects. CONCLUSIONS: Systemic delivery of miR-181b inhibits the activation of NF-kappaB 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. |
