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Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 2021645, 10 pages
Research Article

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

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

Correspondence should be addressed to Brian S. Zuckerbraun; ude.cmpu@sbnuarbrekcuz

Received 20 November 2017; Revised 15 February 2018; Accepted 6 March 2018; Published 12 April 2018

Academic Editor: Antonio Ayala

Copyright © 2018 Paul K. Waltz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.