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The interaction of endothelin-1 and TGF-beta1 mediates vascular cell remodeling

Lambers, C. and Roth, M. and Zhong, J. and Campregher, C. and Binder, P. and Burian, B. and Petkov, V. and Block, L. H.. (2013) The interaction of endothelin-1 and TGF-beta1 mediates vascular cell remodeling. PLoS ONE, Vol. 8, H. 8 , e73399.

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Official URL: http://edoc.unibas.ch/dok/A6338167

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Abstract

BACKGROUND: Pulmonary arterial hypertension is characterized by increased thickness of pulmonary vessel walls due to both increased proliferation of pulmonary arterial smooth muscle cell (PASMC) and deposition of extracellular matrix. In patients suffering from pulmonary arterial hypertension, endothelin-1 (ET-1) synthesis is up-regulated and may increase PASMC activity and vessel wall remodeling through transforming growth factor beta-1 (TGF-beta1) and connective tissue growth factor. OBJECTIVE: To assess the signaling pathway leading to ET-1 induced proliferation and extracellular matrix deposition by human PASMC. METHODS: PASMC were serum starved for 24 hours before stimulation with either ET-1 and/or TGF-beta1. ET-1 was inhibited by Bosentan, ERK1/2 mitogen activated protein kinase (MAPK) was inhibited by U0126 and p38 MAPK was inhibited by SB203580. RESULTS: ET-1 increased PASMC proliferation when combined with serum. This effect involved the mitogen activated protein kinases (MAPK) ERK1/2 MAPK and was abrogated by Bosentan which caused a G1- arrest through activation of p27((Kip)). Regarding the contribution of extracellular matrix deposition in vessel wall remodeling, TGF-beta1 increased the deposition of collagen type-I and fibronectin, which was further increased when ET-1 was added mainly through ERK1/2 MAPK. In contrast, collagen type-IV was not affected by ET-1. Bosentan dose-dependently reduced the stimulatory effect of ET-1 on collagen type-I and fibronectin, but had no effect on TGF-beta1. CONCLUSION AND CLINICAL RELEVANCE: ET-1 alone does not induce PASMC proliferation and extracellular matrix deposition. However, ET-1 significantly up-regulates serum induced proliferation and TGF-beta1 induced extracellular matrix deposition, specifically of collagen type-I and fibronectin. The synergistic effects of ET-1 on serum and TGF-beta1 involve ERK1/2 MAPK and may thus present a novel mode of action in the pathogenesis of pulmonary arterial hypertensi
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Pulmonary Cell Research (Roth/Tamm)
UniBasel Contributors:Roth-Chiarello, Michael
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Public Library of Science
e-ISSN:1932-6203
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 Aug 2018 06:39
Deposited On:10 Apr 2015 09:12

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