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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
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.
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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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