Allen Kaitlin N, Torres-Velarde Julia María, Vazquez Juan Manuel, Moreno-Santillán Diana D, Sudmant Peter H, Vázquez-Medina José Pablo
Department of Integrative Biology, University of California Berkeley, Berkeley, CA, 94720, USA.
Center for Computational Biology, University of California Berkeley, Berkeley, CA, 94720, USA.
BMC Biol. 2024 Apr 23;22(1):91. doi: 10.1186/s12915-024-01892-3.
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.
Seal and human endothelial cells exposed to 1% O 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.
We found that the glutathione antioxidant system is upregulated in seal endothelial 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.
海象表现出极强的低氧耐受性，这源于它们在潜水过程中经历的反复缺氧/复氧事件。由于难以在海上获取样本，对海豹抗缺氧损伤保护机制的分子变化进行实时评估仍然受到限制。因此，我们建立了一种来自海象的增殖性动脉内皮细胞培养模型，并使用RNA测序、功能分析和共聚焦显微镜来评估对长时间缺氧的分子反应。
暴露于1%氧气环境长达6小时的海豹和人类内皮细胞对急性和长时间缺氧的反应不同。海豹细胞将缺氧敏感转录调节因子HIF-1α的稳定性与血管生成信号解耦。参与谷胱甘肽（GSH）代谢的基因迅速上调，支持GSH池的维持，并且海豹细胞内琥珀酸增加，而人类细胞则不然。缺氧暴露后，海豹细胞具有高最大呼吸能力和备用呼吸能力，同时线粒体分支长度增加，且与细胞外酸化率的主要变化无关，这表明海豹细胞在缺氧暴露后恢复氧化代谢，而不依赖于显著的糖酵解。
我们发现，在缺氧期间，海豹内皮细胞中的谷胱甘肽抗氧化系统上调，而在类似的人类细胞中该系统保持不变。此外，我们发现，与人类细胞不同，缺氧暴露会迅速激活海豹细胞中的HIF-1，但这种反应与经典血管生成途径解耦。这些结果突出了在一种顶级潜水哺乳动物中赋予对有限氧气供应非凡耐受性的独特机制。
