JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Diabetes Complications Research Centre, Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
Diabetes. 2017 Aug;66(8):2266-2277. doi: 10.2337/db16-1405. Epub 2017 May 9.
The let-7 miRNA family plays a key role in modulating inflammatory responses. Vascular smooth muscle cell (SMC) proliferation and endothelial cell (EC) dysfunction are critical in the pathogenesis of atherosclerosis, including in the setting of diabetes. Here we report that let-7 levels are decreased in diabetic human carotid plaques and in a model of diabetes-associated atherosclerosis, the diabetic ApoE mouse. In vitro platelet-derived growth factor (PDGF)- and tumor necrosis factor-α (TNF-α)-induced vascular SMC and EC activation was associated with reduced let-7 miRNA expression via Lin28b, a negative regulator of let-7 biogenesis. Ectopic overexpression of let-7 in SMCs inhibited inflammatory responses including proliferation, migration, monocyte adhesion, and nuclear factor-κB activation. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in SMCs using an endogenous anti-inflammatory lipid (lipoxin A), ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease.
let-7 miRNA 家族在调节炎症反应中起着关键作用。血管平滑肌细胞（SMC）增殖和内皮细胞（EC）功能障碍是动脉粥样硬化发病机制中的关键因素，包括在糖尿病的情况下。在这里，我们报告说，let-7 的水平在糖尿病患者的颈动脉斑块和糖尿病相关动脉粥样硬化模型，即糖尿病 ApoE 小鼠中降低。体外血小板衍生生长因子（PDGF）和肿瘤坏死因子-α（TNF-α）诱导的血管 SMC 和 EC 激活与 Lin28b 相关，Lin28b 是 let-7 生物发生的负调节剂，导致 let-7 miRNA 表达减少。SMC 中 let-7 的异位过表达抑制了炎症反应，包括增殖、迁移、单核细胞黏附和核因子-κB 激活。使用 let-7 模拟物恢复 let-7 水平的治疗潜力已通过以下方法进行了测试：在 SMC 中进行体内实验（使用内源性抗炎脂质（脂氧素 A）），在体外进行小鼠主动脉实验，以及在 24 小时的小鼠模型中通过尾静脉注射进行体内实验。此外，我们将 let-7 模拟物递送至人颈动脉斑块进行体外实验，并观察到对 let-7 治疗的分泌组有明显的变化。恢复 let-7 表达可为糖尿病血管疾病的抗炎方法提供新的靶点。
