Hermes-Lima Marcelo, Moreira Daniel C, Rivera-Ingraham Georgina A, Giraud-Billoud Maximiliano, Genaro-Mattos Thiago C, Campos Élida G
Laboratório de Radicais Livres, Departamento de Biologia Celular, Universidade de Brasília, Brasí;lia, DF, 70910-900, Brazil.
Laboratório de Radicais Livres, Departamento de Biologia Celular, Universidade de Brasília, Brasí;lia, DF, 70910-900, Brazil.
Free Radic Biol Med. 2015 Dec;89:1122-43. doi: 10.1016/j.freeradbiomed.2015.07.156. Epub 2015 Sep 25.
Organisms that tolerate wide variations in oxygen availability, especially to hypoxia, usually face harsh environmental conditions during their lives. Such conditions include, for example, lack of food and/or water, low or high temperatures, and reduced oxygen availability. In contrast to an expected strong suppression of protein synthesis, a great number of these animals present increased levels of antioxidant defenses during oxygen deprivation. These observations have puzzled researchers for more than 20 years. Initially, two predominant ideas seemed to be irreconcilable: on one hand, hypoxia would decrease reactive oxygen species (ROS) production, while on the other the induction of antioxidant enzymes would require the overproduction of ROS. This induction of antioxidant enzymes during hypoxia was viewed as a way to prepare animals for oxidative damage that may happen ultimately during reoxygenation. The term "preparation for oxidative stress" (POS) was coined in 1998 based on such premise. However, there are many cases of increased oxidative damage in several hypoxia-tolerant organisms under hypoxia. In addition, over the years, the idea of an assured decrease in ROS formation under hypoxia was challenged. Instead, several findings indicate that the production of ROS actually increases in response to hypoxia. Recently, it became possible to provide a comprehensive explanation for the induction of antioxidant enzymes under hypoxia. The supporting evidence and the limitations of the POS idea are extensively explored in this review as we discuss results from research on estivation and situations of low oxygen stress, such as hypoxia, freezing exposure, severe dehydration, and air exposure of water-breathing animals. We propose that, under some level of oxygen deprivation, ROS are overproduced and induce changes leading to hypoxic biochemical responses. These responses would occur mainly through the activation of specific transcription factors (FoxO, Nrf2, HIF-1, NF-κB, and p53) and post translational mechanisms, both mechanisms leading to enhanced antioxidant defenses. Moreover, reactive nitrogen species are candidate modulators of ROS generation in this scenario. We conclude by drawing out the future perspectives in this field of research, and how advances in the knowledge of the mechanisms involved in the POS strategy will offer new and innovative study scenarios of biological and physiological cellular responses to environmental stress.
能够耐受氧气供应大幅变化，尤其是低氧环境的生物，在其生命过程中通常面临恶劣的环境条件。这些条件包括，例如，缺乏食物和/或水、低温或高温以及氧气供应减少。与预期的蛋白质合成强烈抑制相反，许多这类动物在缺氧期间呈现出抗氧化防御水平的升高。这些观察结果困扰了研究人员二十多年。最初，两个主要观点似乎无法调和：一方面，低氧会减少活性氧（ROS）的产生，而另一方面，抗氧化酶的诱导需要ROS的过量产生。低氧期间抗氧化酶的这种诱导被视为一种让动物为复氧过程中最终可能发生的氧化损伤做好准备的方式。“氧化应激预适应”（POS）这一术语就是基于这样的前提在1998年提出的。然而，在几种耐低氧生物中，有许多情况下在低氧状态下氧化损伤会增加。此外，多年来，低氧状态下ROS形成必然减少的观点受到了挑战。相反，一些研究结果表明，ROS的产生实际上会因低氧而增加。最近，有可能为低氧条件下抗氧化酶的诱导提供一个全面的解释。在本综述中，当我们讨论关于夏眠以及低氧应激情况（如低氧、冷冻暴露、严重脱水和水生动物的空气暴露）的研究结果时，会广泛探讨支持POS观点的证据及其局限性。我们提出，在一定程度的缺氧条件下，ROS会过量产生并引发导致低氧生化反应的变化。这些反应将主要通过特定转录因子（FoxO、Nrf2、HIF-1、NF-κB和p53）的激活以及翻译后机制发生，这两种机制都会导致抗氧化防御增强。此外，在这种情况下，活性氮物种是ROS产生的候选调节因子。我们通过阐述该研究领域的未来前景来结束本文，以及对POS策略所涉及机制的认识进展将如何为生物和生理细胞对环境应激的反应提供新的和创新的研究场景。
