title: Suppression of TAK1 pathway by shear stress counteracts the inflammatory endothelial cell phenotype induced by oxidative stress and TGF-β1.
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-β signalling. While the individual roles of TAK1, ERK5 (MAPK7) and TGF-β 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-β1 on endothelial cells by restoring redox balance and repressing the TAK1 pathway. Using human umbilical vein endothelial cells, we here show that TGF-β1 aggravates oxidative stress-mediated inflammatory activation and that shear stress activates ERK5 signalling while attenuating TGF-β signalling. ERK5 activation restores redox balance, but fails to repress the inflammatory effect of TGF-β1 which is suppressed upon TAK1 inhibition. In conclusion, shear stress counteracts endothelial dysfunction by suppressing the pro-inflammatory non-canonical TGF-β pathway and by activating the ERK5 pathway which restores redox signalling. We propose that a pharmacological compound that abates TGF-β signalling and enhances ERK5 signalling may be useful to counteract endothelial dysfunction.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, NL-9713 GZ, The Netherlands.
authors.forename: Ee Soo
authors.initials: ES
authors.lastname: Lee
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, NL-9713 GZ, The Netherlands.
authors.forename: Llorenç Solé
authors.initials: LS
authors.lastname: Boldo
authors.affiliation: University of Southampton, Southampton General Hospital, Faculty of Medicine, Clinical and Experimental Sciences, Southampton, SO166YD, United Kingdom.
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: University of Southampton, Southampton General Hospital, Faculty of Medicine, Clinical and Experimental Sciences, Southampton, SO166YD, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, NL-9713 GZ, The Netherlands.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Harmsen
mesh_terms: D000818:Animals; D015415:Biomarkers; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D033081:Shear Strength; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D020930:MAP Kinase Kinase Kinases; D048054:Mitogen-Activated Protein Kinase 7; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7