Department of Brain Protection and Plasticity, Institute of Basic Medical Sciences, Taiping Rd 27, Beijing, 100850, People's Republic of China.
Cell Stress Chaperones. 2010 Jul;15(4):387-94. doi: 10.1007/s12192-009-0153-6. Epub 2009 Nov 10.
It has been demonstrated that hypoxic preconditioning (HP) enhances the survival ability of the organism against the subsequent acute anoxia (AA). However, it is not yet clear whether necrosis induced by AA can be prevented by HP, and what are the underlying mechanisms. In this study, we examined the effect of HP (10% O(2), 48 h) on necrosis induced by AA (0% O(2), 24 h) in PC12 cells. We found that HP delayed the regulatory volume decrease and reduced cell swelling after 24 h of exposure to AA. Since aldose reductase (AR) is involved in cell volume regulation, we detected AR mRNA expression with reverse transcription-polymerase chain reaction (RT-PCR) techniques. The AR mRNA level was dramatically elevated by HP. Furthermore, an HP-induced decrease in cell injury was reversed by berberine chloride (BB), the inhibitor of AR. In addition, sorbitol synthesized from glucose catalyzed by AR is directly related to cell volume regulation. Subsequently, we tested sorbitol content in the cytoplasm. HP clearly elevated sorbitol content, while BB inhibited the elevation induced by HP. Further study showed that a strong inhibitor of sorbitol permease, quinidine, completely reversed the protection induced by HP after AA. These data provide evidence that HP prevents necrosis induced by AA and is mediated by AR and sorbitol pathway.
已经证明，低氧预处理（HP）增强了机体对随后的急性缺氧（AA）的存活能力。然而，目前尚不清楚 AA 诱导的细胞坏死是否可以被 HP 预防，以及其潜在机制是什么。在这项研究中，我们研究了 HP（10%O2，48 小时）对 PC12 细胞中 AA（0%O2，24 小时）诱导的坏死的影响。我们发现，HP 延迟了调节性体积减少，并减少了暴露于 AA 24 小时后的细胞肿胀。由于醛糖还原酶（AR）参与细胞体积调节，我们用逆转录-聚合酶链反应（RT-PCR）技术检测 AR mRNA 表达。HP 显著上调了 AR mRNA 水平。此外，AR 的抑制剂小檗碱（BB）逆转了 HP 诱导的细胞损伤减少。另外，由 AR 催化的葡萄糖合成的山梨醇与细胞体积调节直接相关。随后，我们测试了细胞质中山梨醇的含量。HP 明显增加了山梨醇的含量，而 BB 抑制了 HP 诱导的增加。进一步的研究表明，山梨醇通透酶的强抑制剂奎尼丁完全逆转了 AA 后 HP 诱导的保护作用。这些数据提供了证据表明，HP 可以预防 AA 诱导的坏死，并且是由 AR 和山梨醇途径介导的。
