The Endothelial-mesenchymal Transition in Systemic Sclerosis Is Induced by Endothelin-1 and Transforming Growth Factor-β and May Be Blocked by Macitentan, a Dual Endothelin-1 Receptor Antagonist.

Autor:	Cipriani P; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila. paola.cipriani@cc.univaq.it., Di Benedetto P; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Ruscitti P; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Capece D; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Zazzeroni F; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Liakouli V; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Pantano I; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Berardicurti O; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Carubbi F; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Pecetti G; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Turricchia S; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Alesse E; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Iglarz M; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila., Giacomelli R; From the Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, and the Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila, L'Aquila; Medical and Scientific Direction, Actelion Pharmaceuticals Italy, Imola, Italy; Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.P. Cipriani, MD, PhD; P. Di Benedetto, PhD; P. Ruscitti, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; D. Capece, PhD; F. Zazzeroni, PhD, Department of Applied Clinical Sciences and Biotechnology, General Phatology Unit, University of L'Aquila; V. Liakouli, MD, PhD; I. Pantano, MD; O. Berardicurti, MD; F. Carubbi, MD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila; G. Pecetti, MD; S. Turricchia, MD, Medical and Scientific Direction, Actelion Pharmaceuticals Italy; E. Alesse, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, General Pathology Unit, University of L'Aquila; M. Iglarz, PhD, Drug Discovery Department, Actelion Pharmaceuticals Ltd.; R. Giacomelli, MD, PhD, Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila.
Jazyk:	angličtina
Zdroj:	The Journal of rheumatology [J Rheumatol] 2015 Oct; Vol. 42 (10), pp. 1808-16. Date of Electronic Publication: 2015 Aug 15.
DOI:	10.3899/jrheum.150088
Abstrakt:	Objective: High endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) levels may induce in healthy endothelial cells (EC) an endothelial-to-mesenchymal transition (EndMT). The same cytokines are associated with fibrosis development in systemic sclerosis (SSc). Although EndMT has not been definitively shown in SSc, this process, potentially induced by a stimulatory loop involving these 2 cytokines, overexpressed in this disease might contribute to fibroblast accumulation in affected tissues. Macitentan (MAC), an ET-1 receptor antagonist interfering with this loop, might prevent EndMT and fibroblast accumulation. Methods: EC, isolated from healthy controls (HC) and patients with SSc, were treated with ET-1 and TGF-β and successively analyzed for gene and protein expressions of endothelial and mesenchymal markers, and for Sma- and Mad-related (SMAD) phosphorylation. Further, in the supernatants, we evaluated ET-1 and TGF-β production by ELISA assay. In each assay we evaluated the ability of MAC to inhibit both the TGF-β and ET-1 effects. Results: We showed that both TGF-β and ET-1 treatments induced an activation of the EndMT process in SSc-EC as reported in HC cells. The ELISA assays showed a mutual TGF-β and ET-1 induction in both SSc-EC and HC-EC. A statistically significant increase of SMAD phosphorylation after treatment was observed in SSc-EC. In each assay, MAC inhibited both TGF-β and ET-1 effects. Conclusion: Our work is the first demonstration in literature that SSc-EC, under the synergistic effect of TGF-β and ET-1, may transdifferentiate toward myofibroblasts, thus contributing to fibroblast accumulation. MAC, interfering with this process in vitro, may offer a new potential therapeutic strategy against fibrosis.
Databáze:	MEDLINE
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