QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 15, Issue 6, 2707-2719, June 2004

This Article Full Text Full Text (PDF) All Versions of this Article: E03-12-0902v1 15/6/2707    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shi-Wen, X. Articles by Abraham, D. J Search for Related Content PubMed PubMed Citation Articles by Shi-Wen, X. Articles by Abraham, D. J

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

Xu Shi-Wen ^*, Yunliang Chen ^*, Christopher P. Denton ^*, Mark Eastwood , Elisabetta A. Renzoni , George Bou-Gharios , Jeremy D. Pearson ^||, Michael Dashwood ^¶, Roland M. du Bois , Carol M. Black ^*, Andrew Leask ^* #, and David J Abraham ^*

^* 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; and ^¶ Department of Molecular Pathology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom

Submitted December 17, 2003; Revised March 9, 2004; Accepted March 16, 2004
Monitoring Editor: Richard Assoian

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 -smooth muscle actin (-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 -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 -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 -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.

^# Corresponding author. E-mail address: a.leask{at}rfc.ucl.ac.uk.

This article has been cited by other articles:

				C Mihai and J W C Tervaert Anti-endothelial cell antibodies in systemic sclerosis Ann Rheum Dis, February 1, 2010; 69(2): 319 - 324. [Abstract] [Full Text] [PDF]

				X. Shi-wen, M. Eastwood, R. J. Stratton, C. P. Denton, A. Leask, and D. J. Abraham Rosiglitazone alleviates the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts Rheumatology, February 1, 2010; 49(2): 259 - 263. [Abstract] [Full Text] [PDF]

				B. Ross, P. D'Orleans-Juste, and A. Giaid Potential Role of Endothelin-1 in Pulmonary Fibrosis: From the Bench to the Clinic Am. J. Respir. Cell Mol. Biol., January 1, 2010; 42(1): 16 - 20. [Abstract] [Full Text] [PDF]

				P. Kulasekaran, C. A. Scavone, D. S. Rogers, D. A. Arenberg, V. J. Thannickal, and J. C. Horowitz Endothelin-1 and Transforming Growth Factor-{beta}1 Independently Induce Fibroblast Resistance to Apoptosis via AKT Activation Am. J. Respir. Cell Mol. Biol., October 1, 2009; 41(4): 484 - 493. [Abstract] [Full Text] [PDF]

				A. Tyndall, M. Matucci-Cerinic, and U. Muller-Ladner Future targets in the management of systemic sclerosis Rheumatology, June 1, 2009; 48(suppl_3): iii49 - iii53. [Abstract] [Full Text] [PDF]

				S. Liu, M. Kapoor, and A. Leask Rac1 Expression by Fibroblasts Is Required for Tissue Repair in Vivo Am. J. Pathol., May 1, 2009; 174(5): 1847 - 1856. [Abstract] [Full Text] [PDF]

				D. von Lewinski, J. Kockskamper, D. Zhu, H. Post, A. Elgner, and B. Pieske Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na+-Contraction Coupling Circ Heart Fail, January 1, 2009; 2(1): 47 - 55. [Abstract] [Full Text] [PDF]

				T. E. King Jr and R. M. du Bois Elucidating the causes and examining the latest clinical findings in pulmonary fibrosis Eur. Respir. Rev., December 1, 2008; 17(109): 105 - 107. [Full Text] [PDF]

				D. Abraham Role of endothelin in lung fibrosis Eur. Respir. Rev., December 1, 2008; 17(109): 145 - 150. [Abstract] [Full Text] [PDF]

				N. Aden, X. Shiwen, D. Aden, C. Black, A. Nuttall, C. P. Denton, A. Leask, D. Abraham, and R. Stratton Proteomic analysis of scleroderma lesional skin reveals activated wound healing phenotype of epidermal cell layer Rheumatology, December 1, 2008; 47(12): 1754 - 1760. [Abstract] [Full Text] [PDF]

				A. Leask, X. Shi-wen, K. Khan, Y. Chen, A. Holmes, M. Eastwood, C. P. Denton, C. M. Black, and D. J. Abraham Loss of protein kinase C{epsilon} results in impaired cutaneous wound closure and myofibroblast function J. Cell Sci., October 15, 2008; 121(20): 3459 - 3467. [Abstract] [Full Text] [PDF]

				G. S. Bogatkevich, A. Ludwicka-Bradley, C. B. Singleton, J. R. Bethard, and R. M. Silver Proteomic analysis of CTGF-activated lung fibroblasts: identification of IQGAP1 as a key player in lung fibroblast migration Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L603 - L611. [Abstract] [Full Text] [PDF]

				C. F. Opitz, R. Ewert, W. Kirch, and D. Pittrow Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur. Heart J., August 2, 2008; 29(16): 1936 - 1948. [Abstract] [Full Text] [PDF]

				E. Tourkina, M. Richard, P. Gooz, M. Bonner, J. Pannu, R. Harley, P. N. Bernatchez, W. C. Sessa, R. M. Silver, and S. Hoffman Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L843 - L861. [Abstract] [Full Text] [PDF]

				M. Iribarne, L. Ogawa, V. Torbidoni, C. M. Dodds, R. A. Dodds, and A. M. Suburo Blockade of Endothelinergic Receptors Prevents Development of Proliferative Vitreoretinopathy in Mice Am. J. Pathol., April 1, 2008; 172(4): 1030 - 1042. [Abstract] [Full Text] [PDF]

				R. Mishra and M. S. Simonson Oleate Induces a Myofibroblast-Like Phenotype in Mesangial Cells Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 541 - 547. [Abstract] [Full Text] [PDF]

				J. Dupuis and M. M. Hoeper Endothelin receptor antagonists in pulmonary arterial hypertension Eur. Respir. J., February 1, 2008; 31(2): 407 - 415. [Abstract] [Full Text] [PDF]

				M. J. Haurani and P. J. Pagano Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res, September 1, 2007; 75(4): 679 - 689. [Abstract] [Full Text] [PDF]

				R. M. du Bois Blocking endothelin: breaking new ground Eur. Respir. Rev., August 1, 2007; 16(102): 24 - 29. [Abstract] [Full Text] [PDF]

				R. Jain, P. W. Shaul, Z. Borok, and B. C. Willis Endothelin-1 Induces Alveolar Epithelial-Mesenchymal Transition through Endothelin Type A Receptor-Mediated Production of TGF-beta1 Am. J. Respir. Cell Mol. Biol., July 1, 2007; 37(1): 38 - 47. [Abstract] [Full Text] [PDF]

				S. Liu, X. Shi-wen, L. Kennedy, D. Pala, Y. Chen, M. Eastwood, D. E. Carter, C. M. Black, D. J. Abraham, and A. Leask FAK Is Required for TGFbeta-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix-remodeling Phenotype Mol. Biol. Cell, June 1, 2007; 18(6): 2169 - 2178. [Abstract] [Full Text] [PDF]

				H.-R. Kang, C. G. Lee, R. J. Homer, and J. A. Elias Semaphorin 7A plays a critical role in TGF-{beta}1-induced pulmonary fibrosis J. Exp. Med., May 14, 2007; 204(5): 1083 - 1093. [Abstract] [Full Text] [PDF]

				A. Leask TGF{beta}, cardiac fibroblasts, and the fibrotic response Cardiovasc Res, May 1, 2007; 74(2): 207 - 212. [Abstract] [Full Text] [PDF]

				S. He, A. Dibas, T. Yorio, and G. Prasanna Parallel Signaling Pathways in Endothelin-1-Induced Proliferation of U373MG Astrocytoma Cells Exp Biol Med, March 1, 2007; 232(3): 370 - 384. [Abstract] [Full Text] [PDF]

				X. Shi-Wen, F. Rodriguez-Pascual, S. Lamas, A. Holmes, S. Howat, J. D. Pearson, M. R. Dashwood, R. M. du Bois, C. P. Denton, C. M. Black, et al. Constitutive ALK5-Independent c-Jun N-Terminal Kinase Activation Contributes to Endothelin-1 Overexpression in Pulmonary Fibrosis: Evidence of an Autocrine Endothelin Loop Operating through the Endothelin A and B Receptors Mol. Cell. Biol., July 15, 2006; 26(14): 5518 - 5527. [Abstract] [Full Text] [PDF]

				X. Shi-wen, L. A. Stanton, L. Kennedy, D. Pala, Y. Chen, S. L. Howat, E. A. Renzoni, D. E. Carter, G. Bou-Gharios, R. J. Stratton, et al. CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-beta1 in Embryonic Fibroblasts J. Biol. Chem., April 21, 2006; 281(16): 10715 - 10726. [Abstract] [Full Text] [PDF]

				K. R. Stenmark, N. Davie, M. Frid, E. Gerasimovskaya, and M. Das Role of the Adventitia in Pulmonary Vascular Remodeling Physiology, April 1, 2006; 21(2): 134 - 145. [Abstract] [Full Text] [PDF]

				P. Sun, H. Xiong, T. H. Kim, B. Ren, and Z. Zhang Positive Inter-Regulation between beta-Catenin/T Cell Factor-4 Signaling and Endothelin-1 Signaling Potentiates Proliferation and Survival of Prostate Cancer Cells Mol. Pharmacol., February 1, 2006; 69(2): 520 - 531. [Abstract] [Full Text] [PDF]

				Y. Chen, X. Shi-wen, J. van Beek, L. Kennedy, M. McLeod, E. A. Renzoni, G. Bou-Gharios, S. Wilcox-Adelman, P. F. Goetinck, M. Eastwood, et al. Matrix Contraction by Dermal Fibroblasts Requires Transforming Growth Factor-{beta}/Activin-Linked Kinase 5, Heparan Sulfate-Containing Proteoglycans, and MEK/ERK: Insights into Pathological Scarring in Chronic Fibrotic Disease Am. J. Pathol., December 1, 2005; 167(6): 1699 - 1711. [Abstract] [Full Text] [PDF]

				K. Rodgers, B. McMahon, D. Mitchell, D. Sadlier, and C. Godson Lipoxin A4 Modifies Platelet-Derived Growth Factor-Induced Profibrotic Gene Expression in Human Renal Mesangial Cells Am. J. Pathol., September 1, 2005; 167(3): 683 - 694. [Abstract] [Full Text] [PDF]

				C. P. Denton, G. E. Lindahl, K. Khan, X. Shiwen, V. H. Ong, N. J. Gaspar, K. Lazaridis, D. R. Edwards, A. Leask, M. Eastwood, et al. Activation of Key Profibrotic Mechanisms in Transgenic Fibroblasts Expressing Kinase-deficient Type II Transforming Growth Factor-{beta} Receptor (T{beta}RII{Delta}k) J. Biol. Chem., April 22, 2005; 280(16): 16053 - 16065. [Abstract] [Full Text] [PDF]

				Y. Chen, D. J. Abraham, X. Shi-wen, J. D. Pearson, C. M. Black, K. M. Lyons, and A. Leask CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin Mol. Biol. Cell, December 1, 2004; 15(12): 5635 - 5646. [Abstract] [Full Text] [PDF]