Premium
Counter‐regulation of the HIF‐dependent adaptive response to hypoxia by hypercapnia
Author(s) -
Taylor Cormac,
Selfridge Andrew,
Cavadas Miguel,
Scholz Carsten,
Cambpell Eric,
Welch Lynn,
Lecuonah Emilia,
Colgan Sean,
Barrett Kim,
Sporn Peter,
Sznajder Jacob,
Cummins Eoin
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.746.4
Subject(s) - hypercapnia , intracellular ph , hypoxia (environmental) , chemistry , microbiology and biotechnology , acidosis , downregulation and upregulation , intracellular , biochemistry , biology , oxygen , endocrinology , gene , organic chemistry
Molecular O 2 and CO 2 are the primary substrate and product of oxidative metabolism respectively. Hypoxia (low O 2 ) and hypercapnia (high CO 2 ) are co‐incidental features of the microenvironment in a diverse range of pathophysiologic states including cancer, respiratory disease and inflammation. Hypoxia inducible factor (HIF) is the master transcriptional regulator of the response to low oxygen. Despite the close relationship between O 2 and CO 2 levels, the potential impact of CO 2 on HIF remains unclear. Recent studies have demonstrated the ability of CO 2 to regulate gene expression. The purpose of this work was to investigate the effect of hypercapnia on the HIF pathway. HIF‐2α protein and the HIF targets erythropoietin and carbonic anhydrase IX were decreased by hypercapnia in vivo . Hypercapnia suppressed HIF‐1α and HIF‐2α protein stabilization in a variety of cell lines of diverse origin. High CO 2 diminished the activity of HIF‐dependent genes. CO 2 did not impact the canonical, oxygen‐dependent HIF degradation pathway. Hypercapnia caused intracellular acidosis, and levels of HIF‐1/2α protein were lower when intracellular pH (pHi) was reduced by means other than CO 2 . Low pHi is required for optimal lysosomal degradation and a lysosomal inhibitor antagonised the ability of hypercapnia to reduce HIF‐1/2α. In conclusion, we have demonstrated a novel CO 2 ‐dependent suppression of HIF signalling. As HIF regulates the transcription of a host of genes that have angiogenic, glycolytic and inflammatory functions, manipulating HIF with CO 2 could be exploited for therapeutic gain. Support or Funding Information This work was supported by a grant from Science Foundation Ireland (11/PI/1005)