Now showing 1 - 2 of 2
  • Publication
    Regulation of gene expression by carbon dioxide
    (Wiley Blackwell (Blackwell Publishing -The Physiological Society), 2011-01-04) ;
    Carbon dioxide (CO2) is a physiological gas found at low levels in the atmosphere and produced in cells during the process of aerobic respiration. Consequently, the levels of CO2 within tissues are usually significantly higher than those found externally. Shifts in tissue levels of CO2 (leading to either hypercapnia or hypocapnia) are associated with a number of pathophysiological conditions in humans and can occur naturally in niche habitats such as those of burrowing animals. Clinical studies have indicated that such altered CO2 levels can impact upon disease progression. Recent advances in our understanding of the biology of CO2 has shown that like other physiological gases such as molecular oxygen (O2) and nitric oxide (NO), CO2 levels can be sensed by cells resulting in the initiation of physiological and pathophysiological responses. Acute CO2 sensing in neurons and peripheral and central chemoreceptors is important in rapidly activated responses including olfactory signalling, taste sensation and cardiorespiratory control. Furthermore, a role for CO2 in the regulation of gene transcription has recently been identified with exposure of cells and model organisms to high CO2 leading to suppression of genes involved in the regulation of innate immunity and inflammation. This latter, transcriptional regulatory role for CO2, has been largely attributed to altered activity of the NF-κB family of transcription factors. Here, we review our evolving understanding of how CO2 impacts upon gene transcription.
      369Scopus© Citations 34
  • Publication
    Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia
    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.
    Scopus© Citations 45  85