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

• Type of Material: Article
• Authors: Brandy E. Wade, Emory University; Jingru Zhao, Emory University; Jing Ma, Emory University; Michael Hart, Emory University; Roy Sutliff, Emory University
• Language: English
• Date: 2018-09-06
• Publisher: SAGE PUBLICATIONS INC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2018
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1177/2045894018788267
• Title of Journal or Parent Work: PULMONARY CIRCULATION
• Volume: 8
• Issue: 3
• Start Page: 2045894018788267
• End Page: 2045894018788267
• Grant/Funding Information: This work was supported in part by funding from the Department of Veterans Affairs, Biomedical Laboratory Research and Development Office, Merit Review Award (1I01BX001910 to CMH), by NIH NHLBI RO1 (HL102167 to CMH and RLS), and NIH NHLBI T32 (HL076118) and American Heart Association (16POST30930007 to BEW). Research reported in this publication was supported in part by the Emory Integrated Proteomics Core, which is supported by the Emory Neuroscience NINDS Core Facilities (P30NS055077), the Emory University School of Medicine, and represents one of the Emory Integrated Core Facilities (EICF). Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.
• Keywords: INHIBITION; ubiquitin; SMOOTH-MUSCLE-CELLS; ANNEXIN A2; UNITED-STATES; MODELS; proteasome; Life Sciences & Biomedicine; PROMOTES; PROTEOMIC ANALYSIS; Cardiovascular System & Cardiology; Science & Technology; MEDIATED DEGRADATION; EXPRESSION; Cardiac & Cardiovascular Systems; Respiratory System; PROTEIN; hypoxia
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

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.