MicroRNA-181b regulates NF-[kappa]B-mediated vascular inflammation

• Published in: The Journal of clinical investigation Vol. 122; no. 6; p. 1973
• Main Authors: Sun, Xinghui, Icli, Basak, Wara, Akm Khyrul, Belkin, Nathan, He, Shaolin, Kobzik, Lester, Hunninghake, Gary M, Vera, Miguel Pinilla, Blackwell, Timothy S, Baron, Rebecca M, Feinberg, Mark W
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 01.06.2012
• Subjects: Biomedical research; Cytokines; Endothelium; Gene expression; Inflammation; Inflammatory diseases; Kinases; Leukocytes; MicroRNAs; Protein expression; Proteins; Sepsis; T cell receptors
• ISSN: 0021-9738; 1558-8238

EC activation and dysfunction have been linked to a variety of vascular inflammatory disease states. The function of microRNAs (miRNAs) in vascular EC activation and inflammation remains poorly understood. Herein, we report that microRNA-181b (miR-181b) serves as a potent regulator of downstream NF-κB signaling in the vascular endothelium by targeting importin-α3, a protein that is required for nuclear translocation of NF-κB. Overexpression of miR-181b inhibited importin-α3 expression and an enriched set of NF-κB-responsive genes such as adhesion molecules VCAM-1 and E-selectin in ECs in vitro and in vivo. In addition, treatment of mice with proinflammatory stimuli reduced miR-181b expression. Rescue of miR-181b levels by systemic administration of miR-181b "mimics" reduced downstream NF-κB signaling and leukocyte influx in the vascular endothelium and decreased lung injury and mortality in endotoxemic mice. In contrast, miR-181b inhibition exacerbated endotoxin-induced NF-κB activity, Leukocyte influx, and lung injury. Finally, we observed that critically ill patients with sepsis had reduced levels of miR-181b compared with control intensive care unit (ICU) subjects. Collectively, these findings demonstrate that miR-181b regulates NF-κB-mediated EC activation and vascular inflammation in response to proinflammatory stimuli and that rescue of miR-181b expression could provide a new target for antiinflammatory therapy and critical illness. [PUBLICATION ABSTRACT]