MicroRNA-181b regulates NF-κB-mediated vascular inflammation

Xinghui Sun, Basak Icli, Akm Khyrul Wara, Nathan Belkin, Shaolin He, Lester Kobzik, Gary M. Hunninghake, Miguel Pinilla Vera, Timothy S. Blackwell, Rebecca M. Baron, Mark W. Feinberg, Tamas Dolinay, Lee Gazourian, Laura Fredenburgh, Anthony Massaro, Augustine Choi

Research output: Contribution to journalArticle

276 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1973-1990
Number of pages18
JournalJournal of Clinical Investigation
Volume122
Issue number6
DOIs
StatePublished - Jun 1 2012

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MicroRNAs
Blood Vessels
Inflammation
Karyopherins
Vascular Endothelium
Lung Injury
Critical Illness
Leukocytes
E-Selectin
Vascular Cell Adhesion Molecule-1
Vascular Diseases
Endotoxins
Intensive Care Units
Sepsis
Anti-Inflammatory Agents
Mortality
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sun, X., Icli, B., Wara, A. K., Belkin, N., He, S., Kobzik, L., ... Choi, A. (2012). MicroRNA-181b regulates NF-κB-mediated vascular inflammation. Journal of Clinical Investigation, 122(6), 1973-1990. https://doi.org/10.1172/JCI61495

MicroRNA-181b regulates NF-κB-mediated vascular inflammation. / 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.; Dolinay, Tamas; Gazourian, Lee; Fredenburgh, Laura; Massaro, Anthony; Choi, Augustine.

In: Journal of Clinical Investigation, Vol. 122, No. 6, 01.06.2012, p. 1973-1990.

Research output: Contribution to journalArticle

Sun, X, Icli, B, Wara, AK, Belkin, N, He, S, Kobzik, L, Hunninghake, GM, Vera, MP, Blackwell, TS, Baron, RM, Feinberg, MW, Dolinay, T, Gazourian, L, Fredenburgh, L, Massaro, A & Choi, A 2012, 'MicroRNA-181b regulates NF-κB-mediated vascular inflammation', Journal of Clinical Investigation, vol. 122, no. 6, pp. 1973-1990. https://doi.org/10.1172/JCI61495
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. ; Dolinay, Tamas ; Gazourian, Lee ; Fredenburgh, Laura ; Massaro, Anthony ; Choi, Augustine. / MicroRNA-181b regulates NF-κB-mediated vascular inflammation. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 6. pp. 1973-1990.
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