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IL (Interleukin)-6 Contributes to Deep Vein Thrombosis and Is Negatively Regulated by miR-338-5p.
Arteriosclerosis, Thrombosis, and Vascular Biology ( IF 7.4 ) Pub Date : 2019-12-19 , DOI: 10.1161/atvbaha.119.313137
Yunhong Zhang 1, 2 , Zhen Zhang 2 , Ran Wei 2 , Xiuming Miao 3 , Shangwen Sun 2, 4 , Gang Liang 3 , Chu Chu 1, 2 , Lin Zhao 2 , Xiaoxiao Zhu 2 , Qiang Guo 2 , Bin Wang 3 , Xia Li 2
Affiliation  

OBJECTIVE Deep venous thrombosis (DVT), one of the most common venous thromboembolic disorders, is closely linked with pulmonary embolism and post-thrombotic syndrome, both of which have a high mortality. However, the factors that trigger DVT formation are still largely unknown. Elevated expression of IL (interleukin)-6-an important inflammatory cytokine-has been linked with DVT formation. However, the molecular mechanisms leading to the elevated IL-6 in DVT remain unclear. Here, we proposed that epigenetic modification of IL-6 at the post-transcriptional level may be a crucial trigger for IL-6 upregulation in DVT. Approach and Results: To explore the association between microRNAs and IL-6 in DVT, we performed microRNA microarray analysis and experiments both in vitro and in vivo. Microarray and quantitative real-time polymerase chain reaction results showed that IL-6 expression was increased while miR-338-5p level was decreased substantially in peripheral blood mononuclear cells of patients with DVT, and there was significant negative correlation between miR-338-5p and IL-6. Experiments in vitro showed that overexpressed miR-338-5p reduced IL-6 expression, while miR-338-5p knockdown increased IL-6 expression. Moreover, our in vivo study found that mice with anti-IL-6 antibody or agomiR-338-5p delivery resulted in decreased IL-6 expression and alleviated DVT formation, whereas antagomiR-338-5p acted inversely. Most of miR-338-5p was found located in cytoplasm by fluorescence in situ hybridization. Dual-luciferase reporter assay identified direct binding between miR-338-5p and IL-6. CONCLUSIONS Our results suggest that decreased miR-338-5p promotes DVT formation by increasing IL-6 expression.

中文翻译:

IL(白介素)-6促进深静脉血栓形成,并受miR-338-5p负调节。

目的深静脉血栓形成(DVT)是最常见的静脉血栓栓塞性疾病之一,与肺栓塞和血栓形成后综合征密切相关,两者均具有很高的死亡率。但是,触发DVT形成的因素仍然很大程度上未知。IL(白介素)-6(一种重要的炎症细胞因子)的表达升高与DVT的形成有关。但是,尚不清楚导致DVT中IL-6升高的分子机制。在这里,我们提出在转录后水平上IL-6的表观遗传修饰可能是DVT中IL-6上调的关键触发因素。方法和结果:为了探讨DVT中microRNA与IL-6之间的关系,我们进行了microRNA微阵列分析和体内外实验。微阵列和实时定量聚合酶链反应结果表明,DVT患者外周血单个核细胞中IL-6表达增加而miR-338-5p水平显着降低,并且miR-338-5p之间呈显着负相关和IL-6。体外实验表明,过表达的miR-338-5p降低了IL-6的表达,而miR-338-5p的降低则提高了IL-6的表达。此外,我们的体内研究发现,具有抗IL-6抗体或agomiR-338-5p递送的小鼠可导致IL-6表达降低并减轻DVT的形成,而antagomiR-338-5p则起相反的作用。通过荧光原位杂交发现大多数miR-338-5p位于细胞质中。双荧光素酶报告基因分析鉴定了miR-338-5p和IL-6之间的直接结合。
更新日期:2020-01-23
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