Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors.
Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors.
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DOI：
10.3389/fcell.2018.00132
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发表时间：
2018
影响因子：
5.5
通讯作者：
Forsyth NR
中科院分区：
文献类型：
--
作者：
Chen R;Lai UH;Zhu L;Singh A;Ahmed M;Forsyth NR
缺氧诱导因子（HIF）是细胞内主要的氧传感器，在调节细胞对不同氧水平的反应中起着核心作用。缺氧时HIF的激活可确保最佳的ATP生成和细胞完整性，并与活性氧（ROS）的形成直接或间接相关。HIF激活既可以通过抑制线粒体三羧酸循环（TCA循环）功能减少ROS的形成，也可以通过HIF通路靶基因NADPH氧化酶（NOX）增加ROS的形成。活性氧是有氧代谢不可避免的结果。在正常条件下（即生理缺氧），ROS的产生是最低水平的，并作为一种信号分子，受ROS产生和清除之间的专门平衡的影响。氧浓度的变化影响ROS的形成。当ROS水平超过防御机制时，ROS会引起氧化应激。在缺氧和再氧过程中，ROS水平的增加也可能是HIF稳定的一个促进因素。在这篇综述中，我们系统地回顾了缺氧和缺氧/再氧化时大脑中HIF的激活和ROS的形成。然后，我们将探索描述HIF水平变化如何为有效的缺血性卒中治疗提供药理学靶点的文献。通过抑制HIF脯氨酰羟化酶（PHD）在大脑中的积累，除了HIF促生存信号外，还具有抗氧化和抗炎特性，因此被认为是缺血性卒中的有效治疗方法。PHD是细胞中HIF水平的关键调节因子。药物抑制PHD可增加常氧条件下（即20.9% O2水平下）HIF水平。HIF PHD抑制剂预处理在体外和体内缺血脑卒中模型中均显示出神经保护作用，但PHD抑制剂在脑卒中后的治疗仍有争议。再灌注时抑制HIF PHD可减少ROS的形成，激活多种细胞存活途径。鉴于靶向缺血级联中单个分子的药物（例如抗氧化剂）在临床环境中无法翻译，迄今为止，靶向HIF通路并由此影响整个生理网络是减少缺血性卒中不良反应的有希望的药物靶点。
Hypoxia inducible factor (HIF) is the master oxygen sensor within cells and is central to the regulation of cell responses to varying oxygen levels. HIF activation during hypoxia ensures optimum ATP production and cell integrity, and is associated both directly and indirectly with reactive oxygen species (ROS) formation. HIF activation can either reduce ROS formation by suppressing the function of mitochondrial tricarboxylic acid cycle (TCA cycle), or increase ROS formation via NADPH oxidase (NOX), a target gene of HIF pathway. ROS is an unavoidable consequence of aerobic metabolism. In normal conditions (i.e., physioxia), ROS is produced at minimal levels and acts as a signaling molecule subject to the dedicated balance between ROS production and scavenging. Changes in oxygen concentrations affect ROS formation. When ROS levels exceed defense mechanisms, ROS causes oxidative stress. Increased ROS levels can also be a contributing factor to HIF stabilization during hypoxia and reoxygenation. In this review, we systemically review HIF activation and ROS formation in the brain during hypoxia and hypoxia/reoxygenation. We will then explore the literature describing how changes in HIF levels might provide pharmacological targets for effective ischaemic stroke treatment. HIF accumulation in the brain via HIF prolyl hydroxylase (PHD) inhibition is proposed as an effective therapy for ischaemia stroke due to its antioxidation and anti-inflammatory properties in addition to HIF pro-survival signaling. PHD is a key regulator of HIF levels in cells. Pharmacological inhibition of PHD increases HIF levels in normoxia (i.e., at 20.9% O2 level). Preconditioning with HIF PHD inhibitors show a neuroprotective effect in both in vitro and in vivo ischaemia stroke models, but post-stroke treatment with PHD inhibitors remains debatable. HIF PHD inhibition during reperfusion can reduce ROS formation and activate a number of cellular survival pathways. Given agents targeting individual molecules in the ischaemic cascade (e.g., antioxidants) fail to be translated in the clinic setting, thus far, HIF pathway targeting and thereby impacting entire physiological networks is a promising drug target for reducing the adverse effects of ischaemic stroke.
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影响因子：
3.3
作者：
Diebold I;Petry A;Hess J;Görlach A
通讯作者：
Görlach A
影响因子：
5.6
作者：
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影响因子：
64.8
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作者：
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