Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/148358
Title: System-wide molecular dynamics of endothelial dysfunction in Gram-negative sepsis
Authors: Gallart-Palau, Xavier
Serra, Aida
Sze, Siu Kwan
Keywords: Science::Biological sciences
Issue Date: 2020
Source: Gallart-Palau, X., Serra, A. & Sze, S. K. (2020). System-wide molecular dynamics of endothelial dysfunction in Gram-negative sepsis. BMC Biology, 18(1). https://dx.doi.org/10.1186/s12915-020-00914-0
Project: NMRC-OF-IRG-0003-2016
MOE2016-T2-2-018
Journal: BMC biology
Abstract: Background: Inflammation affecting whole organism vascular networks plays a central role in the progression and establishment of several human diseases, including Gram-negative sepsis. Although the molecular mechanisms that control inflammation of specific vascular beds have been partially defined, knowledge lacks on the impact of these on the molecular dynamics of whole organism vascular beds. In this study, we have generated an in vivo model by coupling administration of lipopolysaccharide with stable isotope labeling in mammals to mimic vascular beds inflammation in Gram-negative sepsis and to evaluate its effects on the proteome molecular dynamics. Proteome molecular dynamics of individual vascular layers (glycocalyx (GC), endothelial cells (EC), and smooth muscle cells (SMC)) were then evaluated by coupling differential systemic decellularization in vivo with unbiased systems biology proteomics. Results: Our data confirmed the presence of sepsis-induced disruption of the glycocalyx, and we show for the first time the downregulation of essential molecular maintenance processes in endothelial cells affecting this apicalvascular coating. Similarly, a novel catabolic phenotype was identified in the newly synthesized EC proteomes that involved the impairment of protein synthesis, which affected multiple cellular mechanisms, including oxidative stress, the immune system, and exacerbated EC-specific protein turnover. In addition, several endogenous molecular protective mechanisms involving the synthesis of novel antithrombotic and anti-inflammatory proteins were also identified as active in EC. The molecular dynamics of smooth muscle cells in whole organism vascular beds revealed similar patterns of impairment as those identified in EC, although this was observed to a lesser extent. Furthermore, the dynamics of protein post translational modifications showed disease-specific phosphorylation sites in the EC proteomes. Conclusions: Together, the novel findings reported here provide a broader picture of the molecular dynamics that take place in whole organism vascular beds in Gram-negative sepsis inflammation. Similarly, the obtained data canpave the way for future therapeutic strategies aimed at intervening in specific protein synthesis mechanisms of the vascular unit during acute inflammatory processes.
URI: https://hdl.handle.net/10356/148358
ISSN: 1741-7007
DOI: 10.1186/s12915-020-00914-0
Rights: © 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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