Department of Biological Sciences, University of Alaska Anchorage, Anchorage, AK 99508, United States.
Department of Biological Sciences, University of Alaska Anchorage, Anchorage, AK 99508, United States.
Comp Biochem Physiol A Mol Integr Physiol. 2022 May;267:111167. doi: 10.1016/j.cbpa.2022.111167. Epub 2022 Feb 17.
In anoxia-sensitive mammals, hypoxia inducible factor (HIF) promotes cellular survival in hypoxia, but also tumorigenesis. By comparison, anoxia-tolerant vertebrates likely need to circumvent a prolonged upregulation of HIF to survive long-term anoxia, making them attractive biomedical models for investigating HIF regulation. To lend insight into the role of HIF in anoxic Trachemys scripta ventricle and telencephalon, 21 °C- and 5 °C-acclimated turtles were exposed to normoxia, anoxia (24 h at 21 °C; 24 h or 14 d at 5 °C) or anoxia + reoxygenation and the gene expression of HIF-1α (hif1a) and HIF-2α (hif2a), two regulators of HIF, and eleven putative downstream targets of HIF quantified by qPCR. Changes in gene expression with anoxia at 21 °C differentially aligned with a circumvention of HIF activity. Whereas hif1a and hif2a expression was unaffected in ventricle and telencephalon, and BCL2 interacting protein 3 gene expression reduced by 30% in telencephalon, gene expression of vascular endothelial growth factor-A increased in ventricle (4.5-fold) and telencephalon (1.5-fold), and hexokinase 1 (2-fold) and hexokinase 2 (3-fold) gene expression increased in ventricle. At 5 °C, the pattern of gene expression in ventricle or telencephalon was unaltered with oxygenation state. However, cold acclimation in normoxia induced downregulation of HIF-1α, HIF-2α, and HIF target gene expression in telencephalon. Overall, the findings lend support to the postulation that prolonged activation of HIF is counterproductive for long-term anoxia survival. Nevertheless, quantification of the effect of anoxia and acclimation temperature on HIF binding activity and regulation at the protein level are needed to provide a strong scientific framework whereby new strategies for oxygen related pathologies can be developed.
在缺氧敏感的哺乳动物中，缺氧诱导因子 (HIF) 促进缺氧细胞存活，但也促进肿瘤发生。相比之下，耐缺氧的脊椎动物可能需要避免 HIF 的长期上调以在长期缺氧中存活，这使它们成为研究 HIF 调节的有吸引力的生物医学模型。为了深入了解 HIF 在缺氧的中华鳖心室和大脑中的作用，21°C 和 5°C 驯化的龟分别暴露于常氧、缺氧（21°C 下 24 小时；5°C 下 24 小时或 14 天）或缺氧+复氧，并用 qPCR 定量 HIF-1α（hif1a）和 HIF-2α（hif2a）这两种 HIF 调节剂和 11 种可能的 HIF 下游靶基因的基因表达。21°C 缺氧时基因表达的变化与 HIF 活性的规避不同步。虽然心室和大脑中 hif1a 和 hif2a 的表达不受影响，但大脑中 BCL2 相互作用蛋白 3 的基因表达减少了 30%，而血管内皮生长因子-A 的基因表达在心室（4.5 倍）和大脑（1.5 倍）中增加，并且在心室中己糖激酶 1（2 倍）和己糖激酶 2（3 倍）的基因表达增加。在 5°C 下，无论氧合状态如何，心室或大脑中的基因表达模式均未改变。然而，常氧中的冷驯化诱导了大脑中 HIF-1α、HIF-2α 和 HIF 靶基因表达的下调。总的来说，这些发现支持了这样的假设，即 HIF 的长期激活对长期缺氧生存是适得其反的。然而，需要定量缺氧和驯化温度对 HIF 结合活性和蛋白质水平调节的影响，以提供一个强有力的科学框架，从而可以开发新的与氧气相关的病理学策略。
