Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts
Authors: Andrew Leask
Mark Eastwood
Roland M du Bois
Yunliang Chen
Christopher P Denton
David J Abraham
Jeremy D Pearson
Xu Shi-Wen
Elisabetta A Renzoni
Carol M Black
Michael Dashwood
George Bou-Gharios
Journal: Molecular Biology of the Cell (2004)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Endothelins; vasoconstriction; tissue repair; myofibroblast contraction; matrix remodeling
Affiliations: Centre for Rheumatology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom, Centre for Tissue Engineering Research, University of Westminster, London W1W 6UM, United Kingdom, Interstitial Lung Disease Unit, Royal Brompton Hospital, Imperial College School of Medicine, London SW3 6LR, United Kingdom, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom, Centre for Cardiovascular Biology and Medicine, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London SE1 1UL, United Kingdom, Department of Molecular Pathology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom

Abstract:  The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including alpha-smooth muscle actin (alpha-SMA), ezrin, moesin, and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA, ezrin, paxillin, and moesin and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of alpha-SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma) show enhanced ET-1 expression and binding. Systemic sclerosis lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins alpha-SMA, ezrin, paxillin, and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis. 

Retracted: No

PubPeer comments:
 I hope that the closing sentence is not simply there as a citation plantation. These are [very familiar References] .  In addition, this work can also provide new ideas to the fields, such as degradation of antibiotic and organic materials [19], - [19] Yuan D L, Zhang C, Tang S F, Sun M T, Zhang Y T, Rao Y D et al 2020 Sci. Total Environ. 727 138773 ** Fe3+-sulfite complexation enhanced persulfate Fenton-like process for antibiotic degradation based on response surface optimization **  and the treatment of wastewater [34u201336], - [34] Yu F K, Wang Y, Ma H R and Zhou M H 2020 Sep. Purif. Technol. 248 117022 ** Hydrothermal synthesis of FeS2 as a highly efficient heterogeneous electro-Fenton catalyst to degrade diclofenac via molecular oxygen effects for Fe(II) Fe(III) Cycle ** - [35] Duan C, Yu Y, Li J, Li L, Huang B, Chen D et al 2021 Sci. China Mater ** Recent advances in the synthesis of monolithic metal-organic frameworks ** - [36] Tang S F, Wang Z T, Yuan D L, Zhang C, Rao Y D, Wang Z B et al 2020 J. Clean. Prod. 268 122253 ** Ferrous ion-tartaric acid chelation promoted calcium peroxide fenton-like reactions for simulated organic wastewater treatment **  acid water [37], - [37] Tang S F, Tang J C, Yuan D L, Wang Z T, Zhang Y T and Rao Y D 2020 RSC Adv. 10 17627 ** Elimination of humic acid in water: comparison of UV PDS and UV PMS **  electrocatalysis [38u201340] - [38] Jiang N, Liu Y, Yu X N, Zhang H B and Wang M M 2020 Int. J. Electrochem. Sci. 15 5520 ** Corrosion Resistance of Nickel-Phosphorus Nano-ZnO Composite Multilayer Coating Electrodeposited on Carbon Steel in Acidic Chloride Environments  ** [39] Yuan D L, Sun M T, Zhao M Z, Tamg S F, Qi J B, Zhang X Y et al 2020 Int. J. Electrochem. Sci. 15 8761 ** Persulfate Promoted ZnIn2S4 Visible Light Photocatalytic Dye Decomposition ** [40] Yu F, Chen Y, Pan Y, Yang Y and Ma H 2020 Sep. Purif. Technol. 241 116695 ** A cost-effective production of hydrogen peroxide via improved mass transfer of oxygen for electro-Fenton process using the vertical flow reactor **  and photocatalysis [41]. - [41] Duan C, Dong L, Li F, Xie Y, Huang B, Wang K et al 2020 Ind. Eng. Chem. Res. 59 18857 ** Room-Temperature Rapid Synthesis of Two-Dimensional Metalu2013Organic Framework Nanosheets with Tunable Hierarchical Porosity for Enhanced Adsorption Desulfurization Performance. ** It is difficult to see what new ideas could be brought to this eclectic but irrelevant parade of topics. ,