miR-374b-5p is increased in deep vein thrombosis and negatively targets IL-10

Yunhong Zhang, Xiuming Miao, Zhen Zhang, Ran Wei, Shangwen Sun, Gang Liang, Huihan Li, Chu Chu, Lin Zhao, Xiaoxiao Zhu, Qiang Guo, Bin Wang, Xia Li
Journal of Molecular and Cellular Cardiology2020
Background: Deep venous thrombosis (DVT) is one of the most common venous thromboembolic (VTE) disorders and the third leading cardiovascular complication. Accumulating evidence has shown that decreased interleukin- 10 (IL-10) was involved in DVT. However, the underlying molecular mechanisms are still largely unknown. Here, we proposed that the epigenetic modification of IL-10 at the post-transcriptional level may be a crucial trigger for IL-10 down-regulation in DVT. Methods: miRNA expression in DVT was profiled by miRNA microarray analysis. The upstream miRNA reg- ulators of IL-10 were predicted by in silico target prediction tools. The expression of IL-10 mRNA and miR-374b- 5p were examined by quantitative real-time PCR (qRT-PCR) and the protein expression of IL-10 was detected by enzyme-linked immunoassay. Dual luciferase reporter assay was used to identify the interaction between miR- 374b-5p and IL10. A murine model of DVT was developed and the localization of miR-374b-5p was visualized in vitro by fluorescence in situ hybridization. The biological effects of miR-374b-5p on IL-10 was examined both in vitro and in vivo. Results: Microarray and qRT-PCR results showed that the IL-10 expression was decreased while miR-374b-5p level was increased substantially in peripheral blood mononuclear cells of DVT patients, and there was sig- nificant negative correlation between miR-374b-5p and IL-10. Experiments in vitro showed that overexpressed miR-374b-5p reduced IL-10 expression, while miR-374b-5p knockdown increased IL-10 expression. Moreover, in vivo studies revealed that DVT mice with anti-IL-10 antibody or agomiR-374b-5p delivery resulted in decreased IL-10 expression and aggravated DVT formation, whereas antagomiR-374b-5p acted inversely. Dual luciferase reporter assay identified direct binding between miR-374b-5p and IL10. Conclusions: These findings suggest that increased miR-374b-5p promotes DVT formation by downregulating IL- 10 expression. miR-374b-5p may be explored as a promising diagnostic marker and therapeutic target for DVT. Abbreviations:

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