MicroRNA‐181b inhibits thrombin‐mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10

作者：Jibin Lin, Shaolin He, Xinghui Sun, G Franck, Yihuan Deng, Dafeng Yang, Stefan Haemmig, Akm Khyrul Wara, Basak Icli, Dazhu Li, Mark W. Feinberg · 发表于：The FASEB Journal · 年份：2016 · DOI：10.1096/fj.201500163r · 被引用次数：47 · 研究领域：Blood Coagulation and Thrombosis Mechanisms、Cancer-related molecular mechanisms research、NF-κB Signaling Pathways

Thrombogenic and inflammatory mediators, such as thrombin, induce NF-κB-mediated endothelial cell (EC) activation and dysfunction, which contribute to pathogenesis of arterial thrombosis. The role of anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Our previous study demonstrated that miR-181b inhibits downstream NF-κB signaling in response to TNF-α. Here, we demonstrate that miR-181b uniquely inhibits upstream NF-κB signaling in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-κB signaling, demonstrated by reduction of phospho-IKK-β, -IκB-α, and p65 nuclear translocation in ECs. MiR-181b also reduced expression of NF-κB target genes VCAM-1, intercellular adhesion molecule-1, E-selectin, and tissue factor. Mechanistically, miR-181b targets caspase recruitment domain family member 10 (Card10), an adaptor protein that participates in activation of the IKK complex in response to signals transduced from protease-activated receptor-1. miR-181b reduced expression of Card10 mRNA and protein, but not protease-activated receptor-1. 3'-Untranslated region reporter assays, argonaute-2 microribonucleoprotein immunoprecipitation studies, and Card10 rescue studies revealed that Card10 is a bona fide direct miR-181b target. Small interfering RNA-mediated knockdown of Card10 expression phenocopied effects of miR-181b on NF-κB signaling and targets. Card10 deficiency did not affect TNF-α-induced activation of NF-κB signaling...