Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

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Title: Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia
Authors: 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.
Sznajder, Jacob I.
Cummins, Eoin P.
Taylor, Cormac T.
Permanent link: http://hdl.handle.net/10197/9155
Date: 27-May-2016
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-α 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-α 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-α 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-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: American Society for Biochemistry and Molecular Biology
Copyright (published version): 2016 The American Society for Biochemistry and Molecular Biology
Keywords: Carbon dioxide;Chronic obstructive pulmonary disease (COPD);Erythropoiesis;Hypercapnia;Hypoxia;Hypoxia-Inducible Factor (HIF);Oxygen
DOI: 10.1074/jbc.M116.713941
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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