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Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia


Selfridge, Andrew C; Cavadas, Miguel A S; Scholz, Carsten C; Campbell, Eric L; Welch, Lynn C; Lecuona, Emilia; Colgan, Sean P; Barrett, Kim E; Sporn, Peter H S; Sznajder, Jacob I; Cummins, Eoin P; Taylor, Cormac T (2016). Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia. Journal of Biological Chemistry, 22(291):11800-11808.

Abstract

Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-alpha protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-alpha protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-alpha protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-alpha subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.

Abstract

Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-alpha protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-alpha protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-alpha protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-alpha subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2016
Deposited On:24 Jun 2016 12:23
Last Modified:04 Aug 2017 14:10
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in Journal Name. Selfridge A C et al. Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia. Journal of Biological Chemistry. 2016; 291:11800-11808 © the American Society for Biochemistry and Molecular Biology.
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M116.713941
Related URLs:http://www.jbc.org/content/291/22/11800.long (Publisher)
PubMed ID:27044749

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