Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals.
BACKGROUND: Elephant seals exhibit extreme hypoxemic tolerance derived from repetitive hypoxia/reoxygenation episodes they experience during diving bouts. Real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessib...
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ftcdlib:oai:escholarship.org:ark:/13030/qt8t95v46f 2024-05-19T07:39:43+00:00 Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. Allen, Kaitlin Torres-Velarde, Julia Vazquez, Juan Moreno-Santillán, Diana Sudmant, Peter Vázquez-Medina, José 2024-04-23 application/pdf https://escholarship.org/uc/item/8t95v46f unknown eScholarship, University of California qt8t95v46f https://escholarship.org/uc/item/8t95v46f public Journal of Biology, vol 22, iss 1 Diving Glutathione Inflammation Ischemia/reperfusion Marine mammal Redox Animals Seals Earless Endothelial Cells Antioxidants Up-Regulation Signal Transduction Humans Hypoxia Cell Hypoxia Neovascularization Physiologic Cells Cultured Hypoxia-Inducible Factor 1 alpha Subunit article 2024 ftcdlib 2024-04-30T23:35:08Z BACKGROUND: Elephant seals exhibit extreme hypoxemic tolerance derived from repetitive hypoxia/reoxygenation episodes they experience during diving bouts. Real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture model from elephant seals and used RNA-seq, functional assays, and confocal microscopy to assess the molecular response to prolonged hypoxia. RESULTS: Seal and human endothelial cells exposed to 1% O2 for up to 6h respond differently to acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1α from angiogenic signaling. Rapid upregulation of genes involved in glutathione (GSH) metabolism supports the maintenance of GSH pools, and intracellular succinate increases in seal but not human cells. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurs in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting that seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. CONCLUSIONS: We found that the glutathione antioxidant system is upregulated in sealendothelial cells during hypoxia, while this system remains static in comparable human cells. Furthermore, we found that in contrast to human cells, hypoxia exposure rapidly activates HIF-1 in seal cells, but this response is decoupled from the canonical angiogenesis pathway. These results highlight the unique mechanisms that confer extraordinary tolerance to limited oxygen availability in a champion diving mammal. Article in Journal/Newspaper Elephant Seals University of California: eScholarship |
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Open Polar |
collection |
University of California: eScholarship |
op_collection_id |
ftcdlib |
language |
unknown |
topic |
Diving Glutathione Inflammation Ischemia/reperfusion Marine mammal Redox Animals Seals Earless Endothelial Cells Antioxidants Up-Regulation Signal Transduction Humans Hypoxia Cell Hypoxia Neovascularization Physiologic Cells Cultured Hypoxia-Inducible Factor 1 alpha Subunit |
spellingShingle |
Diving Glutathione Inflammation Ischemia/reperfusion Marine mammal Redox Animals Seals Earless Endothelial Cells Antioxidants Up-Regulation Signal Transduction Humans Hypoxia Cell Hypoxia Neovascularization Physiologic Cells Cultured Hypoxia-Inducible Factor 1 alpha Subunit Allen, Kaitlin Torres-Velarde, Julia Vazquez, Juan Moreno-Santillán, Diana Sudmant, Peter Vázquez-Medina, José Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. |
topic_facet |
Diving Glutathione Inflammation Ischemia/reperfusion Marine mammal Redox Animals Seals Earless Endothelial Cells Antioxidants Up-Regulation Signal Transduction Humans Hypoxia Cell Hypoxia Neovascularization Physiologic Cells Cultured Hypoxia-Inducible Factor 1 alpha Subunit |
description |
BACKGROUND: Elephant seals exhibit extreme hypoxemic tolerance derived from repetitive hypoxia/reoxygenation episodes they experience during diving bouts. Real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture model from elephant seals and used RNA-seq, functional assays, and confocal microscopy to assess the molecular response to prolonged hypoxia. RESULTS: Seal and human endothelial cells exposed to 1% O2 for up to 6h respond differently to acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1α from angiogenic signaling. Rapid upregulation of genes involved in glutathione (GSH) metabolism supports the maintenance of GSH pools, and intracellular succinate increases in seal but not human cells. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurs in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting that seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. CONCLUSIONS: We found that the glutathione antioxidant system is upregulated in sealendothelial cells during hypoxia, while this system remains static in comparable human cells. Furthermore, we found that in contrast to human cells, hypoxia exposure rapidly activates HIF-1 in seal cells, but this response is decoupled from the canonical angiogenesis pathway. These results highlight the unique mechanisms that confer extraordinary tolerance to limited oxygen availability in a champion diving mammal. |
format |
Article in Journal/Newspaper |
author |
Allen, Kaitlin Torres-Velarde, Julia Vazquez, Juan Moreno-Santillán, Diana Sudmant, Peter Vázquez-Medina, José |
author_facet |
Allen, Kaitlin Torres-Velarde, Julia Vazquez, Juan Moreno-Santillán, Diana Sudmant, Peter Vázquez-Medina, José |
author_sort |
Allen, Kaitlin |
title |
Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. |
title_short |
Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. |
title_full |
Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. |
title_fullStr |
Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. |
title_full_unstemmed |
Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. |
title_sort |
hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals. |
publisher |
eScholarship, University of California |
publishDate |
2024 |
url |
https://escholarship.org/uc/item/8t95v46f |
genre |
Elephant Seals |
genre_facet |
Elephant Seals |
op_source |
Journal of Biology, vol 22, iss 1 |
op_relation |
qt8t95v46f https://escholarship.org/uc/item/8t95v46f |
op_rights |
public |
_version_ |
1799479299733979136 |