Suppression of TAK1 pathway by shear stress counteracts the inflammatory endothelial cell phenotype induced by oxidative stress and TGF-β1

Lee, Ee Soo, Boldo, Llorenç Solé, Fernandez, Bernadette O, Feelisch, Martin and Harmsen, Martin C (2017) Suppression of TAK1 pathway by shear stress counteracts the inflammatory endothelial cell phenotype induced by oxidative stress and TGF-β1. Scientific Reports, 7, [42487]. (doi:10.1038/srep42487).

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.

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Contributors

Author: Bernadette O Fernandez

Author: Martin Feelisch

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