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Oxid Med Cell Longev. 2018 Apr 12;2018:2021645. doi: 10.1155/2018/2021645. eCollection 2018.

Heme Oxygenase-2 Localizes to Mitochondria and Regulates Hypoxic Responses in Hepatocytes.

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Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.


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-1α protein levels and JNK signaling. Methods and Results. In vitro studies 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-1α and 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.

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