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Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis

Pulmonary hypertension (PH) is a clinical disorder characterized by sustained increases in pulmonary vascular resistance and pressure that can lead to right ventricular (RV) hypertrophy and ultimately RV failure and death. The molecular pathogenesis of PH remains incompletely defined, and existing t...

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Autores principales: Wade, Brandy E., Zhao, Jingru, Ma, Jing, Hart, C. Michael, Sutliff, Roy L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146334/
https://www.ncbi.nlm.nih.gov/pubmed/29927354
http://dx.doi.org/10.1177/2045894018788267
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author Wade, Brandy E.
Zhao, Jingru
Ma, Jing
Hart, C. Michael
Sutliff, Roy L.
author_facet Wade, Brandy E.
Zhao, Jingru
Ma, Jing
Hart, C. Michael
Sutliff, Roy L.
author_sort Wade, Brandy E.
collection PubMed
description Pulmonary hypertension (PH) is a clinical disorder characterized by sustained increases in pulmonary vascular resistance and pressure that can lead to right ventricular (RV) hypertrophy and ultimately RV failure and death. The molecular pathogenesis of PH remains incompletely defined, and existing treatments are associated with suboptimal outcomes and persistent morbidity and mortality. Reports have suggested a role for the ubiquitin proteasome system (UPS) in PH, but the extent of UPS-mediated non-proteolytic protein alterations during PH pathogenesis has not been previously defined. To further examine UPS alterations, the current study employed C57BL/6J mice exposed to normoxia or hypoxia for 3 weeks. Lung protein ubiquitination was evaluated by mass spectrometry to identify differentially ubiquitinated proteins relative to normoxic controls. Hypoxia stimulated differential ubiquitination of 198 peptides within 131 proteins (p < 0.05). These proteins were screened to identify candidates within pathways involved in PH pathogenesis. Some 51.9% of the differentially ubiquitinated proteins were implicated in at least one known pathway contributing to PH pathogenesis, and 13% were involved in three or more PH pathways. Anxa2, App, Jak1, Lmna, Pdcd6ip, Prkch1, and Ywhah were identified as mediators in PH pathways that undergo differential ubiquitination during PH pathogenesis. To our knowledge, this is the first study to report global changes in protein ubiquitination in the lung during PH pathogenesis. These findings suggest signaling nodes that are dynamically regulated by the UPS during PH pathogenesis. Further exploration of these differentially ubiquitinated proteins and related pathways can provide new insights into the role of the UPS in PH pathogenesis.
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spelling pubmed-61463342018-09-21 Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis Wade, Brandy E. Zhao, Jingru Ma, Jing Hart, C. Michael Sutliff, Roy L. Pulm Circ Research Article Pulmonary hypertension (PH) is a clinical disorder characterized by sustained increases in pulmonary vascular resistance and pressure that can lead to right ventricular (RV) hypertrophy and ultimately RV failure and death. The molecular pathogenesis of PH remains incompletely defined, and existing treatments are associated with suboptimal outcomes and persistent morbidity and mortality. Reports have suggested a role for the ubiquitin proteasome system (UPS) in PH, but the extent of UPS-mediated non-proteolytic protein alterations during PH pathogenesis has not been previously defined. To further examine UPS alterations, the current study employed C57BL/6J mice exposed to normoxia or hypoxia for 3 weeks. Lung protein ubiquitination was evaluated by mass spectrometry to identify differentially ubiquitinated proteins relative to normoxic controls. Hypoxia stimulated differential ubiquitination of 198 peptides within 131 proteins (p < 0.05). These proteins were screened to identify candidates within pathways involved in PH pathogenesis. Some 51.9% of the differentially ubiquitinated proteins were implicated in at least one known pathway contributing to PH pathogenesis, and 13% were involved in three or more PH pathways. Anxa2, App, Jak1, Lmna, Pdcd6ip, Prkch1, and Ywhah were identified as mediators in PH pathways that undergo differential ubiquitination during PH pathogenesis. To our knowledge, this is the first study to report global changes in protein ubiquitination in the lung during PH pathogenesis. These findings suggest signaling nodes that are dynamically regulated by the UPS during PH pathogenesis. Further exploration of these differentially ubiquitinated proteins and related pathways can provide new insights into the role of the UPS in PH pathogenesis. SAGE Publications 2018-06-21 /pmc/articles/PMC6146334/ /pubmed/29927354 http://dx.doi.org/10.1177/2045894018788267 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Research Article
Wade, Brandy E.
Zhao, Jingru
Ma, Jing
Hart, C. Michael
Sutliff, Roy L.
Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis
title Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis
title_full Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis
title_fullStr Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis
title_full_unstemmed Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis
title_short Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis
title_sort hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146334/
https://www.ncbi.nlm.nih.gov/pubmed/29927354
http://dx.doi.org/10.1177/2045894018788267
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