The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension.
Autor: | Schlueter BC; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany., Quanz K; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany., Baldauf J; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany., Petrovic A; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany., Ruppert C; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany., Guenther A; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany; Agaplesion Lung Clinic Waldhof-Elgershausen, Greifenstein 35753, Germany., Gall H; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany; University Hospital Giessen and Marburg (UKGM), Giessen 35392, Germany., Tello K; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany; University Hospital Giessen and Marburg (UKGM), Giessen 35392, Germany., Grimminger F; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany; University Hospital Giessen and Marburg (UKGM), Giessen 35392, Germany., Ghofrani HA; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany; University Hospital Giessen and Marburg (UKGM), Giessen 35392, Germany., Weissmann N; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany., Seeger W; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany; Max Planck Institute (MPI) for Heart and Lung Research, Parkstrasse 1, Bad Nauheim 61231, Germany; University Hospital Giessen and Marburg (UKGM), Giessen 35392, Germany., Schermuly RT; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany., Weiss A; Justus-Liebig-University Giessen (JLU), Aulweg 130, Giessen 35392, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Giessen 35392, Germany; Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896, Giessen 35392, Germany; Member of the German Center for Lung Research (DZL), Giessen 35392, Germany. Electronic address: astrid.weiss@innere.med.uni-giessen.de. |
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Jazyk: | angličtina |
Zdroj: | Vascular pharmacology [Vascul Pharmacol] 2024 Jun; Vol. 155, pp. 107379. Date of Electronic Publication: 2024 May 16. |
DOI: | 10.1016/j.vph.2024.107379 |
Abstrakt: | Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular pathologies and IGF-binding proteins (IGFBPs) are important regulators of the bioavailability and function of IGFs. In this study, we show that circulating plasma levels of IGFBP-1, IGFBP-2 and IGFBP-3 are increased in idiopathic pulmonary arterial hypertension (IPAH) patients compared to healthy individuals. These binding proteins inhibit the IGF-1 induced IGF-1 receptor (IGF1R) phosphorylation and exhibit diverging effects on the IGF-1 induced signaling pathways in human pulmonary arterial cells (i.e. healthy as well as IPAH-hPASMCs, and healthy hPAECs). Furthermore, IGFBPs are differentially expressed in an experimental mouse model of PH. In hypoxic mouse lungs, IGFBP-1 mRNA expression is decreased whereas the mRNA for IGFBP-2 is increased. In contrast to IGFBP-1, IGFBP-2 shows vaso-constrictive properties in the murine pulmonary vasculature. Our analyses show that IGFBP-1 and IGFBP-2 exhibit diverging effects on IGF-1 signaling and display a unique IGF1R-independent kinase activation pattern in human pulmonary arterial smooth muscle cells (hPASMCs), which represent a major contributor of PAH pathobiology. Furthermore, we could show that IGFBP-2, in contrast to IGFBP-1, induces epidermal growth factor receptor (EGFR) signaling, Stat-3 activation and expression of Stat-3 target genes. Based on our results, we conclude that the IGFBP family, especially IGFBP-1, IGFBP-2 and IGFBP-3, are deregulated in PAH, that they affect IGF signaling and thereby regulate the cellular phenotype in PH. Competing Interests: Declaration of competing interest The following authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Beate Christiane Schlueter, Karin Quanz, Julia Baldauf, Aleksandar Petrovic, Clemens Ruppert, Andreas Guenther, Henning Gall, Khodr Tello, Friedrich Grimminger, Hossein-Ardeschir Ghofrani, Norbert Weissmann, Ralph Theo Schermuly, Astrid Weiss. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Werner Seeger received consulting fees from United Therapeutics, Tiakis Biotech AG, Liquidia, Pieris Pharmaceuticalsm Abivax, Pfitzer, Medspray BV. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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