Abstract 12669: Microrna-181b Inhibits Endothelial NF-?B Signaling, Insulin Resistance, and Atherosclerosis
Rationale: Activated NF-κB signaling in the vascular endothelium promotes the initiation and progression of insulin resistance and atherosclerosis (athero). Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation.
Objective: To examine the role of miR-181b in endothelial NF-κB signaling, athero and insulin resistance.
Methods and results: MiR-181b expression was reduced in the aortic intima in ApoE-/- mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease (CAD) compared to subjects without focal obstructive CAD. Systemic delivery of miR-181b resulted in a 2.3-fold miR-181b over-expression in the aortic intima of ApoE-/- mice without altering miR-181a and miR-181c expression. MiR-181b suppressed NF-κB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in ApoE-/-/NF-κB luciferase transgenic mice. MiR-181b inhibited atherosclerotic lesion formation (aortic sinus and thoracic-abdominal aorta), pro-inflammatory gene expression (VCAM-1, E-selectin, ICAM-1, TNF-α, and IL-1β), 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, 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 for miR-181b’s effects. Finally, miR-181b protected mice from insulin resistance in diet-induced obesity of C57BL/6 mice.
Conclusion: Systemic delivery of miR-181b inhibits vascular endothelial NF-κB activation, insulin resistance, and athero through cell-specific mechanisms. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases such as athero and diabetes.
- © 2013 by American Heart Association, Inc.