Data from: Hypoxia blunts angiogenic signaling and upregulates the antioxidant system in elephant seal endothelial cells

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 6 h 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 seal 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 HIF-angiogenesis pathway. These results
highlight the unique mechanisms that confer extraordinary tolerance to
limited oxygen availability in a champion diving mammal.

研究背景：象海豹在潜水过程中会反复经历缺氧/复氧循环，因此演化出极强的低氧耐受能力。
然而，由于象海豹难以在野外（海上）获取样本，对其低氧损伤保护相关分子机制的实时评估始终受限。
为此，我们建立了增殖型象海豹动脉内皮细胞体外培养模型，并通过RNA测序（RNA-seq）、功能实验以及共聚焦显微镜，探究其在长期低氧环境下的分子应答反应。

实验结果：将象海豹与人类内皮细胞分别置于1%氧浓度环境中培养6小时，二者对急性及长期低氧的应答存在显著差异。
象海豹细胞将低氧敏感型转录调控因子缺氧诱导因子-1α（HIF-1α）的稳定化过程与血管生成信号通路解耦。
谷胱甘肽（GSH）代谢相关基因的快速上调，有助于维持细胞内GSH储备；同时象海豹细胞内的琥珀酸水平会升高，而人类细胞则无此变化。
低氧暴露后，象海豹细胞具备更高的最大呼吸容量与储备呼吸容量，这一现象与线粒体分支长度增加同步发生，且不受细胞外酸化率的显著变化影响，表明象海豹细胞在低氧暴露后可恢复氧化代谢，且无需显著依赖糖酵解途径。

研究结论：我们发现，低氧环境下象海豹细胞内的谷胱甘肽抗氧化系统会被上调，而人类同源细胞中的该系统则保持稳态。
此外，与人类细胞不同，低氧暴露会快速激活象海豹细胞内的HIF-1，但该应答过程并不依赖经典的HIF-血管生成通路。
本研究揭示了这种顶尖潜水哺乳动物应对氧气限制的独特耐受机制。