Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., S.H., A.K.M.W., B.I., E.S., Y.T., N.B., G.K.S., K.C., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (S.H., D.L.); and Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (T.S.B.).
Circ Res. 2014 Jan 3;114(1):32-40. doi: 10.1161/CIRCRESAHA.113.302089. Epub 2013 Oct 1.
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.
To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis.
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.
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.
血管内皮细胞中激活的核因子 (NF)-κB 信号转导可促进动脉粥样硬化的发生和进展。针对内皮 NF-κB 可能提供一种限制慢性炎症的新策略。
研究 microRNA-181b (miR-181b) 在血管内皮 NF-κB 信号转导中的作用及其对动脉粥样硬化的影响。
高脂饮食喂养的载脂蛋白 E 缺陷小鼠主动脉内膜和血浆中 miR-181b 表达减少。相应地，人类冠心病患者循环血浆中的 miR-181b 明显减少。miR-181b 的系统给药导致载脂蛋白 E 缺陷小鼠主动脉内膜中的 miR-181b 表达增加 2.3 倍，并通过生物发光成像抑制 NF-κB 信号转导，并减少载脂蛋白 E 缺陷/NF-κB-荧光素酶转基因小鼠主动脉弓中的靶基因表达。miR-181b 显著抑制动脉粥样硬化病变形成、促炎基因表达以及病变血管壁中巨噬细胞和 CD4+T 细胞的流入。在机制上，miR-181b 抑制靶基因 importin-α3 的表达，这一作用可特异性抑制病变血管内皮中的 NF-κB 核易位，尽管 miR-181b 的表达增加了 7 倍，但白细胞 NF-κB 信号转导不受影响。我们的发现揭示了白细胞中 NF-κB 核易位不涉及 miR-181b 不针对的 importin-α5，而是 importin-α3，这突出表明抑制内皮细胞中的 NF-κB 信号转导足以介导 miR-181b 的保护作用。
系统给予 miR-181b 通过血管内皮中的细胞特异性机制抑制 NF-κB 的激活和动脉粥样硬化。这些发现支持这样一种观点，即给予 miR-181b 可能为治疗动脉粥样硬化等慢性炎症性疾病提供一种新的治疗方法。
