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Untargeted metabolomics of HUVECs subjected to hypoxia-reoxygenation

ABSTRACT: 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 (increasing lysophospholipids), promoting the interaction of MMP24 and MMP25 with glycocalyx constituents. In trauma patients, we found that succinate levels were associated with glycocalyx damage and the development of coagulopathy, and that interaction of MMP24 and syndecan-1 were elevated compared to healthy controls. This establishes a novel metabolic cascade mediating the endotheliopathy of traumatic hemorrhage.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cultured Cells

DISEASE(S): Hypoxia

SUBMITTER: Olan Jackson-Weaver

PROVIDER: ST002461 | MetabolomicsWorkbench | Mon Jan 30 00:00:00 GMT 2023

REPOSITORIES: MetabolomicsWorkbench

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