Heme Oxygenase-2 Localizes to Mitochondria and Regulates Hypoxic Responses in Hepatocytes.
Heme Oxygenase-2 Localizes to Mitochondria and Regulates Hypoxic Responses in Hepatocytes.
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血红素加氧酶 2 定位于线粒体并调节肝细胞的缺氧反应。
DOI：
10.1155/2018/2021645
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发表时间：
2018
影响因子：
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通讯作者：
Zuckerbraun,BrianS
中科院分区：
文献类型：
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作者：
Waltz,PaulK;Kautza,Benjamin;Luciano,Jason;Dyer,Mitch;Stolz,DonnaBeer;Loughran,Patricia;Neal,MatthewD;Sperry,JasonL;Rosengart,MatthewR;Zuckerbraun,BrianS
缺氧是多种疾病状态的一部分，包括失血性休克。细胞内发生适应性反应以限制缺氧的后果。这包括线粒体呼吸、应激诱导的细胞信号传导以及受缺氧诱导因子-1α (HIF-1α) 调节的基因表达的变化。血红素加氧酶-2 (HO-2) 已被证明参与多种细胞类型的氧传感。这些实验的目的是检验以下假设：HO-2 是线粒体耗氧量和活性氧 (ROS) 产生的关键调节因子，可影响缺氧适应性反应，例如 HIF-1α 蛋白水平和 JNK 信号传导。方法和结果。在原代小鼠肝细胞中进行体外研究。基线时线粒体中表达 HO-2，但不表达 HO-1。缺氧时耗氧量的减少和线粒体 ROS 产生的增加取决于 HO-2 的表达。 HO-2 表达以线粒体 ROS 依赖性方式调节 HIF-1α 和 JNK 信号传导。此外，在出血和复苏的小鼠模型中，HO-2 的敲低导致器官损伤、全身炎症、组织缺氧和休克增加。结论。 HO-2 信号在缺氧信号和失血性休克中发挥作用。该途径可能能够用于治疗效果。
Hypoxia occurs as a part of multiple disease states, including hemorrhagic shock. Adaptive responses occur within the cell to limit the consequences of hypoxia. This includes changes in mitochondrial respiration, stress‐induced cell signaling, and gene expression that is regulated by hypoxia inducible factor‐1α(HIF‐1α). Heme oxygenase‐2 (HO‐2) has been shown to be involved in oxygen sensing in several cell types. The purpose of these experiments was to test the hypothesis that HO‐2 is a critical regulator of mitochondrial oxygen consumption and reactive oxygen species (ROS) production to influence hypoxia‐adaptive responses such as HIF‐1αprotein levels and JNK signaling.Methods and Results.In vitrostudies were performed in primary mouse hepatocytes. HO‐2, but not HO‐1, was expressed in mitochondria at baseline. Decreased oxygen consumption and increased mitochondrial ROS production in response to hypoxia were dependent upon HO‐2 expression. HO‐2 expression regulated HIF‐1αand JNK signaling in a mitochondrial ROS‐dependent manner. Furthermore, knockdown of HO‐2 led to increased organ damage, systemic inflammation, tissue hypoxia, and shock in a murine model of hemorrhage and resuscitation.Conclusion. HO‐2 signaling plays a role in hypoxic signaling and hemorrhagic shock. This pathway may be able to be harnessed for therapeutic effects.