Type

Journal Article

Authors

Cormac T Taylor
Eoin P Cummins
Jacob I Sznajder
Peter H S Sporn
Kim E Barrett
Sean P Colgan
Emilia Lecuona
Lynn C Welch
Eric L Campbell
Carsten C Scholz
and 2 others

Subjects

Biochemistry

Topics
chronic obstructive pulmonary disease copd hypercapnia oxygen hif cells cultured adaptive erythropoiesis hypoxia protein stability hypoxia inducible factor hif carbon dioxide

Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia. (2016)

Abstract Molecular oxygen and carbon dioxide are the primary 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 in 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 constant pCO2. 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.
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Full list of authors on original publication

Cormac T Taylor, Eoin P Cummins, Jacob I Sznajder, Peter H S Sporn, Kim E Barrett, Sean P Colgan, Emilia Lecuona, Lynn C Welch, Eric L Campbell, Carsten C Scholz and 2 others

Experts in our system

1
Cormac T. Taylor
University College Dublin
Total Publications: 110
 
2
Eoin P. Cummins
University College Dublin
Total Publications: 53
 
3
Sean P. Colgan
University College Dublin
Total Publications: 7
 
4
Eric L Campbell
Maynooth University
Total Publications: 10
 
5
Carsten C Scholz
University College Dublin
Total Publications: 21