Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-2
Section snippets
Materials and methods
Mice. HO-2−/− mice with C57/BL6J × 129/Sv mixed genetic background were generated as previously described [26]. Male homozygous HO-2−/− mice were backcrossed with female C57/BL6J mice. After the backcross for 6 generations, heterozygous HO-2 mice were intercrossed and their littermates were used for this study. HO-2 genotyping was determined by a pair of PCR primers, which spans neomycin-resistant cassette: 5′-GCTTGGGTGGAGAGGCTATTC-3′ and 5′-CAAGGTGAGATGACAGGAGATC-3′ using genomic DNA prepared
Hypoxemia in HO-2−/− mice
The identity of the HO-2−/− mice was confirmed by the genotype analysis (data not shown). We also analyzed the expression of HO-2 protein in the testis, where HO-2 protein is abundantly expressed [34]. We prepared an antibody specific to a mouse HO-2 peptide for the immunohistochemical analysis, because a commercially available anti-HO-2 antibody caused high background staining. Western blot analysis detected HO-2 protein only in the tissue extracts from the testes of wild-type littermates (HO-2
Discussion
Here we have identified hitherto unrecognized phenotypic alterations related to oxygen sensing in HO-2−/− mice. The small magnitude of the hypoxemia may be accounted for by the notions that oxygen homeostasis is essential for all living organisms and must be maintained by multiple factors through separate mechanisms. Generally, the phenotypes of the gene-deficient mice reflect the consequences of various compensatory adaptations that occur during embryogenesis to assure their survival. In this
Acknowledgements
We thank Dr. Poss K.D. for providing HO-2−/− mice and Dr. Lusis A.J. for helping backcross these mice. This work was supported in part by Grants-in-Aid for Scientific Research (B) (to S.S.), for Exploratory Research (to S.S.), and for Priority Area (to S.S.) from the Ministry of Education, Science, Sports and Culture of Japan (12670683 and 14570682 to K.I.), and by the 21st Century COE Program Special Research Grant “the Center for Innovative Therapeutic Development for Common Diseases” from
References (42)
Endogenous carbon monoxide in control of respiration
Respir. Physiol.
(1998)- et al.
Microsomal heme oxygenase. Characterization of the enzyme
J. Biol. Chem.
(1969) - et al.
Nucleotide sequence and organization of the rat heme oxygenase gene
J. Biol. Chem.
(1987) - et al.
Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible
J. Biol. Chem.
(1986) - et al.
Evidence suggesting that the two forms of heme oxygenase and products of different genes
J. Biol. Chem.
(1988) - et al.
Heme oxygenase-2. Properties of the heme complex and purified tryptic peptide of human heme oxygenase-2 expressed in Escherichia coli
J. Biol. Chem.
(1995) - et al.
Transcriptional control of rat heme oxygenase by heat shock
J. Biol. Chem.
(1987) - et al.
Separate regulation of heme oxygenase and heat shock protein 70 mRNA expression in the rat heart by hemodynamic stress
Biochem. Biophys. Res. Commun.
(1993) - et al.
Repression of heme oxygenase-1 by hypoxia in vascular endothelial cells
Biochem. Biophys. Res. Commun.
(2000) - et al.
Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells
J. Biol. Chem.
(2003)
Heme oxygenase-2 is a hemoprotein and binds heme through heme regulatory motifs that are not involved in heme catalysis
J. Biol. Chem.
Hippocampal long-term potentiation is normal in heme oxygenase-2 mutant mice
Neuron
Oxygen sensing in airway chemoreceptors
Nature
Airway chemotransduction: from oxygen sensor to cellular effector
Am. J. Respir. Crit. Care Med.
The mechanism(s) of hypoxic pulmonary vasoconstriction: potassium channels, redox O(2) sensors, and controversies
News Physiol. Sci.
The heme oxygenase dilemma in cellular homeostasis: new insights for the feedback regulation of heme catabolism
Tohoku J. Exp. Med.
The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase
Proc. Natl. Acad. Sci. USA
Cloning and expression of cDNA for rat heme oxygenase
Proc. Natl. Acad. Sci. USA
Rapid induction of heme oxygenase 1 mRNA and protein by hyperthermia in rat brain: heme oxygenase 2 is not a heat shock protein
Proc. Natl. Acad. Sci. USA
Suppression of heme oxygenase-1 mRNA expression by interferon-γ in human glioblastoma cells
J. Neurochem.
Functional analysis of cDNAs for two types of human heme oxygenase and evidence for their separate regulation
J. Biochem. (Tokyo)
Cited by (0)
- 1
Both the authors contributed equally to this work.