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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.

Author information

1
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
2
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
3
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
4
Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
5
VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.

Abstract

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.

PMID:
29849867
PMCID:
PMC5925001
DOI:
10.1155/2018/2021645
[Indexed for MEDLINE]
Free PMC Article

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