Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/148358
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dc.contributor.authorGallart-Palau, Xavieren_US
dc.contributor.authorSerra, Aidaen_US
dc.contributor.authorSze, Siu Kwanen_US
dc.date.accessioned2021-04-29T00:48:10Z-
dc.date.available2021-04-29T00:48:10Z-
dc.date.issued2020-
dc.identifier.citationGallart-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/s12915-020-00914-0en_US
dc.identifier.issn1741-7007en_US
dc.identifier.urihttps://hdl.handle.net/10356/148358-
dc.description.abstractBackground: 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.en_US
dc.description.sponsorshipMinistry of Education (MOE)en_US
dc.description.sponsorshipNational Medical Research Council (NMRC)en_US
dc.language.isoenen_US
dc.relationNMRC-OF-IRG-0003-2016en_US
dc.relationMOE2016-T2-2-018en_US
dc.relation.ispartofBMC biologyen_US
dc.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.en_US
dc.subjectScience::Biological sciencesen_US
dc.titleSystem-wide molecular dynamics of endothelial dysfunction in Gram-negative sepsisen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.identifier.doi10.1186/s12915-020-00914-0-
dc.description.versionPublished versionen_US
dc.identifier.pmid33234129-
dc.identifier.scopus2-s2.0-85096601072-
dc.identifier.issue1en_US
dc.identifier.volume18en_US
dc.subject.keywordsVascular Bedsen_US
dc.subject.keywordsLipopolysaccharideen_US
dc.description.acknowledgementSupport for this work was provided by the National Medical Research Council of Singapore (NMRC-OF-IRG-0003-2016), Ministry of Education of Singapore (MOE2016-T2-2-018), and the Research and Education Council of the Comunidad de Madrid, Spain (2018-T1/BIO-10633). Dr. Aida Serra acknowledges a grant from the Talento Program 2018 of the Comunidad de Madrid, and Dr. Xavier Gallart-Palau acknowledges a grant from the Sara Borrell Program (CD19/00243) of the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded on the 2019 call under the Health Strategy Action 2017–2020 (This grant is co-funded with European Union ERDF Funds (European Regional Development Fund)).en_US
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