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Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage
Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinat...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266735/ https://www.ncbi.nlm.nih.gov/pubmed/37315138 http://dx.doi.org/10.1126/sciadv.adf6600 |
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author | Abdullah, Sarah Ghio, Michael Cotton-Betteridge, Aaron Vinjamuri, Aditya Drury, Robert Packer, Jacob Aras, Oguz Friedman, Jessica Karim, Mardeen Engelhardt, David Kosowski, Emma Duong, Kelby Shaheen, Farhana McGrew, Patrick R. Harris, Charles T. Reily, Robert Sammarco, Mimi Chandra, Partha K. Pociask, Derek Kolls, Jay Katakam, Prasad V. Smith, Alison Taghavi, Sharven Duchesne, Juan Jackson-Weaver, Olan |
author_facet | Abdullah, Sarah Ghio, Michael Cotton-Betteridge, Aaron Vinjamuri, Aditya Drury, Robert Packer, Jacob Aras, Oguz Friedman, Jessica Karim, Mardeen Engelhardt, David Kosowski, Emma Duong, Kelby Shaheen, Farhana McGrew, Patrick R. Harris, Charles T. Reily, Robert Sammarco, Mimi Chandra, Partha K. Pociask, Derek Kolls, Jay Katakam, Prasad V. Smith, Alison Taghavi, Sharven Duchesne, Juan Jackson-Weaver, Olan |
author_sort | Abdullah, Sarah |
collection | PubMed |
description | Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls. |
format | Online Article Text |
id | pubmed-10266735 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-102667352023-06-15 Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage Abdullah, Sarah Ghio, Michael Cotton-Betteridge, Aaron Vinjamuri, Aditya Drury, Robert Packer, Jacob Aras, Oguz Friedman, Jessica Karim, Mardeen Engelhardt, David Kosowski, Emma Duong, Kelby Shaheen, Farhana McGrew, Patrick R. Harris, Charles T. Reily, Robert Sammarco, Mimi Chandra, Partha K. Pociask, Derek Kolls, Jay Katakam, Prasad V. Smith, Alison Taghavi, Sharven Duchesne, Juan Jackson-Weaver, Olan Sci Adv Biomedicine and Life Sciences Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls. American Association for the Advancement of Science 2023-06-14 /pmc/articles/PMC10266735/ /pubmed/37315138 http://dx.doi.org/10.1126/sciadv.adf6600 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Abdullah, Sarah Ghio, Michael Cotton-Betteridge, Aaron Vinjamuri, Aditya Drury, Robert Packer, Jacob Aras, Oguz Friedman, Jessica Karim, Mardeen Engelhardt, David Kosowski, Emma Duong, Kelby Shaheen, Farhana McGrew, Patrick R. Harris, Charles T. Reily, Robert Sammarco, Mimi Chandra, Partha K. Pociask, Derek Kolls, Jay Katakam, Prasad V. Smith, Alison Taghavi, Sharven Duchesne, Juan Jackson-Weaver, Olan Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage |
title | Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage |
title_full | Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage |
title_fullStr | Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage |
title_full_unstemmed | Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage |
title_short | Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage |
title_sort | succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266735/ https://www.ncbi.nlm.nih.gov/pubmed/37315138 http://dx.doi.org/10.1126/sciadv.adf6600 |
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