MicroRNA-17-3p suppresses NF-κB-mediated endothelial inflammation by targeting NIK and IKKβ binding protein  

作　　者：Yin Cai Yu Zhang Hui Chen Xing-hui Sun Peng Zhang Lu Zhang Meng-yang Liao Fang Zhang Zheng-yuan Xia Ricky Ying-keung Man Mark WFeinberg Susan Wai-Sum Leung 

机构地区：[1]Department of Pharmacology and Pharmacy,The University of Hong Kong,Hong Kong,China [2]Department of Health Technology and Informatics,The Hong Kong Polytechnic University,Hong Kong,China [3]Department of Anaesthesiology,The University of Hong Kong,Hong Kong,China [4]Department of Medicine,Cardiovascular Division,Brigham and Women’s Hospital,Harvard Medical School,Boston,MA,USA [5]Department of Cardiology,Institute of Cardiovascular Diseases,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [6]Department of Pharmacology,Medical College of Qingdao University,Qingdao 266021,China

出　　处：《Acta Pharmacologica Sinica》2021年第12期2046-2057,共12页中国药理学报（英文版）

基　　金：supported by the Health and Medical Research Fund(16151212)of the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region(to SWSL);a Seed Fund for Basic Research of the University of Hong Kong(to SWSL);the National Institutes of Health(HL115141,HL117994,HL134849,and GM115605 to MWF);the Arthur K.Watson Charitable Trust(to MWF);the Dr.Ralph&Marian Falk Medical Research Trust(to MWF).

摘　　要：Nuclear factor kappa B(NF-κB)activation contributes to many vascular inflammatory diseases.The present study tested the hypothesis that microRNA-17-3p(miR-17-3p)suppresses the pro-inflammatory responses via NF-κB signaling in vascular endothelium.Human umbilical vein endothelial cells(HUVECs),transfected with or without miR-17-3p agomir/antagomir,were exposed to lipopolysaccharide(LPS),and the inflammatory responses were determined.The cellular target of miR-17-3p was examined with dual-luciferase reporter assay.Mice were treated with miR-17-3p agomir and the degree of LPS-induced inflammation was determined.In HUVECs,LPS caused upregulation of miR-17-3p.Overexpression of miR-17-3p in HUVECs inhibited NIK and IKKβ binding protein(NIBP)protein expression and suppressed LPS-induced phosphorylation of inhibitor of kappa Bα(IκBα)and NF-κB-p65.The reduced NF-κB activity was paralleled by decreased protein levels of NF-κB-target gene products including pro-inflammatory cytokine[interleukin 6],chemokines[interleukin 8 and monocyte chemoattractant protein-1]and adhesion molecules[vascular cell adhesion molecule-1,intercellular adhesion molecule-1 and E-selectin].Immunostaining revealed that overexpression of miR-17-3p reduced monocyte adhesion to LPS-stimulated endothelial cells.Inhibition of miR-17-3p with antagomir has the opposite effect on LPS-induced inflammatory responses in HUVECs.The anti-inflammatory effect of miR-17-3p was mimicked by NIBP knockdown.In mice treated with LPS,miR-17-3p expression was significantly increased.Systemic administration of miR-17-3p for 3 days suppressed LPS-induced NF-κB activation and monocyte adhesion to endothelium in lung tissues of the mice.In conclusion,miR-17-3p inhibits LPS-induced NF-κB activation in HUVECs by targeting NIBP.The findings therefore suggest that miR-17-3p is a potential therapeutic target/agent in the management of vascular inflammatory diseases.

关 键 词：endothelial cells INFLAMMATION miR-17-3p NIK and IKKβbinding protein nuclear factor kappa B 

分 类 号：R965[医药卫生—药理学]