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Title: Suppression of TAK1 pathway by shear stress counteracts the inflammatory endothelial cell phenotype induced by oxidative stress and TGF-?1
Authors: Lee, E.S 
Boldo, L.S
Fernandez, B.O
Feelisch, M
Harmsen, M.C
Keywords: autacoid
biological marker
immunoglobulin enhancer binding protein
MAP kinase kinase kinase 7
mitogen activated protein kinase 7
mitogen activated protein kinase kinase kinase
reactive oxygen metabolite
transforming growth factor beta1
biological model
drug effect
endothelium cell
oxidative stress
shear strength
signal transduction
umbilical vein endothelial cell
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Inflammation Mediators
MAP Kinase Kinase Kinases
Mitogen-Activated Protein Kinase 7
Models, Biological
NF-kappa B
Oxidative Stress
Reactive Oxygen Species
Shear Strength
Signal Transduction
Transforming Growth Factor beta1
Issue Date: 2017
Citation: Lee, E.S, Boldo, L.S, Fernandez, B.O, Feelisch, M, Harmsen, M.C (2017). Suppression of TAK1 pathway by shear stress counteracts the inflammatory endothelial cell phenotype induced by oxidative stress and TGF-?1. Scientific Reports 7 : 42487. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Endothelial dysfunction is characterised by aberrant redox signalling and an inflammatory phenotype. Shear stress antagonises endothelial dysfunction by increasing nitric oxide formation, activating anti-inflammatory pathways and suppressing inflammatory pathways. The TAK1 (MAP3K7) is a key mediator of inflammation and non-canonical TGF-? signalling. While the individual roles of TAK1, ERK5 (MAPK7) and TGF-? pathways in endothelial cell regulation are well characterised, an integrative understanding of the orchestration of these pathways and their crosstalk with the redox system under shear stress is lacking. We hypothesised that shear stress counteracts the inflammatory effects of oxidative stress and TGF-?1 on endothelial cells by restoring redox balance and repressing the TAK1 pathway. Using human umbilical vein endothelial cells, we here show that TGF-?1 aggravates oxidative stress-mediated inflammatory activation and that shear stress activates ERK5 signalling while attenuating TGF-? signalling. ERK5 activation restores redox balance, but fails to repress the inflammatory effect of TGF-?1 which is suppressed upon TAK1 inhibition. In conclusion, shear stress counteracts endothelial dysfunction by suppressing the pro-inflammatory non-canonical TGF-? pathway and by activating the ERK5 pathway which restores redox signalling. We propose that a pharmacological compound that abates TGF-? signalling and enhances ERK5 signalling may be useful to counteract endothelial dysfunction. © The Author(s) 2017.
Source Title: Scientific Reports
ISSN: 20452322
DOI: 10.1038/srep42487
Rights: Attribution 4.0 International
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