title: MicroRNA-181b regulates NF-κB-mediated vascular inflammation.
abstract: 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.
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xinghui
authors.initials: X
authors.lastname: Sun
authors.forename: Basak
authors.initials: B
authors.lastname: Icli
authors.forename: Akm Khyrul
authors.initials: AK
authors.lastname: Wara
authors.forename: Nathan
authors.initials: N
authors.lastname: Belkin
authors.forename: Shaolin
authors.initials: S
authors.lastname: He
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.forename: Gary M
authors.initials: GM
authors.lastname: Hunninghake
authors.forename: Miguel Pinilla
authors.initials: MP
authors.lastname: Vera
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Baron
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000818:Animals; D016638:Critical Illness; D019040:E-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019446:Endotoxemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014657:Vasculitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D028901:alpha Karyopherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D019040:E-Selectin; C106259:KPNA4 protein, human; D008070:Lipopolysaccharides; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D028901:alpha Karyopherins; C523975:importin alpha 3, mouse