title: Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia.
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.
authors.affiliation: From the School of Medicine and Medical Science, Conway Institute, and.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Selfridge
authors.affiliation: Conway Institute, and Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Miguel A S
authors.initials: MA
authors.lastname: Cavadas
authors.affiliation: From the School of Medicine and Medical Science, Conway Institute, and Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland, the Institute of Physiology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Carsten C
authors.initials: CC
authors.lastname: Scholz
authors.affiliation: the University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.affiliation: the Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Welch
authors.affiliation: the Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Emilia
authors.initials: E
authors.lastname: Lecuona
authors.affiliation: the University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.affiliation: From the School of Medicine and Medical Science, Conway Institute, and.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Barrett
authors.affiliation: the Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
authors.forename: Peter H S
authors.initials: PH
authors.lastname: Sporn
authors.affiliation: the Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.affiliation: From the School of Medicine and Medical Science, Conway Institute, and.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.affiliation: From the School of Medicine and Medical Science, Conway Institute, and Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland, cormac.taylor@ucd.ie.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002245:Carbon Dioxide / Q000097:blood*; D002478:Cells, Cultured; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002245:Carbon Dioxide; D010100:Oxygen
keywords: carbon dioxide; chronic obstructive pulmonary disease (COPD); erythropoiesis; hypercapnia; hypoxia; hypoxia-inducible factor (HIF); oxygen