MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy
MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy
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DOI：
10.1161/circresaha.117.311428
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发表时间：
2018-02-02
影响因子：
20.1
通讯作者：
Grundmann, Sebastian
中科院分区：
文献类型：
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作者：
Pankratz, Franziska;Hohnloser, Catherine;Grundmann, Sebastian
目的：本研究旨在研究血管内皮细胞miR-100在血管炎症和动脉粥样硬化形成中的作用。方法和结果：通过对miR-100过表达后内皮细胞的转录组分析，我们发现miR-100是内皮细胞黏附分子表达的有效抑制因子，导致体外和体内白细胞-内皮相互作用减弱，如流式细胞仪和活体成像所示。在机制上，miR-100直接抑制哺乳动物雷帕霉素复合体1信号转导靶点的几个组分，包括哺乳动物雷帕霉素靶点和Raptor，从而在体外和体内刺激内皮自噬和减弱核因子B信号转导。在低密度脂蛋白受体缺陷的动脉粥样硬化小鼠模型中，miR-100的药物抑制导致斑块病变形成增加和斑块中巨噬细胞含量增加，而全身miR-100替代治疗具有保护作用和减轻动脉粥样硬化形成，导致斑块面积减少45%。最后，对颈动脉内膜切除术中70例标本miR-100表达的分析表明，患者局部miR-100的表达与炎性细胞含量呈负相关。结论：综上所述，我们描述了miR-100在血管损伤和炎症反应中的抗炎功能，并确定了雷帕霉素信号转导和血管系统自噬这一哺乳动物靶标的重要新调节因子。我们将miR-100作为一种潜在的保护性抗动脉粥样硬化的miR的发现表明，这种microRNA的治疗性替代可能是未来治疗慢性炎症性疾病(如动脉粥样硬化)的潜在策略。
Rationale: The interaction of circulating cells within the vascular wall is a critical event in chronic inflammatory processes, such as atherosclerosis, but the control of the vascular inflammatory state is still largely unclear.Objective: This study was undertaken to characterize the function of the endothelial-enriched microRNA miR-100 during vascular inflammation and atherogenesis.Methods and Results: Based on a transcriptome analysis of endothelial cells after miR-100 overexpression, we identified miR-100 as a potent suppressor of endothelial adhesion molecule expression, resulting in attenuated leukocyte-endothelial interaction in vitro and in vivo as shown by flow cytometry and intravital imaging. Mechanistically, miR-100 directly repressed several components of mammalian target of rapamycin complex 1-signaling, including mammalian target of rapamycin and raptor, which resulted in a stimulation of endothelial autophagy and attenuated nuclear factor B signaling in vitro and in vivo. In a low-density lipoprotein receptor-deficient atherosclerotic mouse model, pharmacological inhibition of miR-100 resulted in enhanced plaque lesion formation and a higher macrophage content of the plaque, whereas a systemic miR-100 replacement therapy had protective effects and attenuated atherogenesis, resulting in a decrease of plaque area by 45%. Finally, analysis of miR-100 expression in >70 samples obtained during carotid endarterectomy revealed that local miR-100 expression was inversely correlated with inflammatory cell content in patients.Conclusions: In summary, we describe an anti-inflammatory function of miR-100 in the vascular response to injury and inflammation and identify an important novel modulator of mammalian target of rapamycin signaling and autophagy in the vascular system. Our findings of miR-100 as a potential protective anti-athero-miR suggest that the therapeutic replacement of this microRNA could be a potential strategy for the treatment of chronic inflammatory diseases, such as atherosclerosis, in the future.