Connexin40 controls endothelial activation by dampening NFkB activation.

File Description SizeFormat 
16438-241803-1-PB.pdfPublished version8.95 MBAdobe PDFView/Open
Title: Connexin40 controls endothelial activation by dampening NFkB activation.
Authors: Denis, JF
Scheckenbach, KL
Pfenniger, A
Meens, MJ
Krams, R
Miquerol, L
Taffet, S
Chanson, M
Delmar, M
Kwak, BR
Item Type: Journal Article
Abstract: Connexins are proteins forming gap junction channels for intercellular communication. Connexin40 (Cx40) is highly expressed by endothelial cells (ECs) of healthy arteries but this expression is lost in ECs overlying atherosclerotic plaques. Low/oscillatory shear stress observed in bends and bifurcations of arteries is atherogenic partly through activation of the pro-inflammatory NFκB pathway in ECs. In this study, we investigated the relation between shear stress, Cx40 and NFκB. Shear stress-modifying casts were placed around carotid arteries of mice expressing eGFP under the Cx40 promoter (Cx40+/eGFP). We found that Cx40 expression is decreased in carotid regions of oscillatory shear stress but conserved in high and low laminar shear stress regions. These results were confirmed in vitro. Using phage display, we retrieved a binding motif for the intracellular regulatory Cx40 C-terminus (Cx40CT), i.e. HS[I, L, V][K, R]. One of the retrieved peptides (HSLRPEWRMPGP) showed a 58.3% homology with amino acids 5-to-16 of IκBα, a member of the protein complex inhibiting NFκB activation. Binding of IκBα (peptide) and Cx40 was confirmed by crosslinking and en face proximity ligation assay on carotid arteries. TNFα-induced nuclear translocation of NFκB in ECs was enhanced after reducing Cx40 with siRNA. Transfection of HeLa cells with either full-length Cx40 or Cx40CT demonstrated that Cx40CT was sufficient for inhibition of TNFα-induced NFκB phosphorylation. Finally, Tie2CreTgCx40fl/flApoe-/- mice showed exaggerated shear stress-induced atherosclerosis and enhanced NFκB nuclear translocation. Our data show a novel functional IκBα-Cx40 interaction that may be relevant for the control of NFκB activation by shear stress in atherogenesis.
Issue Date: 22-Mar-2017
Date of Acceptance: 27-Feb-2017
URI: http://hdl.handle.net/10044/1/46085
DOI: https://dx.doi.org/10.18632/oncotarget.16438
ISSN: 1949-2553
Publisher: Impact Journals
Start Page: 50972
End Page: 50986
Journal / Book Title: Oncotarget
Volume: 8
Copyright Statement: © 2017 The Author(s). This article is licensed under a Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/).
Sponsor/Funder: British Heart Foundation
British Heart Foundation
British Heart Foundation
CHUV
British Heart Foundation
British Heart Foundation
Funder's Grant Number: PG/08/053/25192
PG/09/090/28065
RG/11/13/29055
CRS113/141811/1
PG/15/49/31595
SP/17/1/32702
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
atherosclerosis
endothelium
Cx40
shear stress
I kappa B alpha
GAP-JUNCTION CHANNELS
ATHEROSCLEROTIC LESION FORMATION
HEMODYNAMIC SHEAR-STRESS
DISTURBED FLOW
PROTEIN CX37
IN-VIVO
EXPRESSION
CELLS
MICE
VULNERABILITY
IκBα
Publication Status: Published
Appears in Collections:Faculty of Engineering
Bioengineering



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commonsx