Role of HIF and Prolyl-hydroxylase enzymes in ventilatory acclimatisation to hypoxia.

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics

Abstract

Oxygen is essential for most forms of life. Even brief periods without oxygen can cause serious tissue damage or death. In humans the supply of oxygen to tissues is provided by the coordinated operation of lungs, heart & blood supply. The effectiveness with which the lungs load oxygen into the blood is monitored by oxygen sensors located close to major arteries (arterial chemoreceptors). If the body is subject to low levels of oxygen (hypoxia) for prolonged periods of time these chemoreceptors become progressively more sensitive to the lack of oxygen and promote a sustained increase in breathing. This process, called ventilatory acclimatisation, helps us to adapt to changes in environmental oxygen availability such as occur when we go to altitude. Indeed this is one of a number of adaptations that are essential for anyone attempting the assent of very high mountains. Similar changes also occur in some disease states but under these circumstances the effects of enhanced chemoreceptor activity are not always desirable. Our research therefore seeks to understand the mechanisms responsible for ventilatory acclimatisation. In particular we wish to test the hypothesis that oxygen dependent control of gene expression, a process very similar to that which gives rise to increase in the number of red blood cells in hypoxia, also controls chemoreceptor sensitivity.

Technical Summary

The body?s supply of oxygen is managed through the controlled operation of both respiratory and cardiovascular systems. The efficacy of oxygen uptake is monitored by arterial chemoreceptors which, in response to acute hypoxia, evoke a robust increase in ventilation. This response helps defend against asphyxia. With more prolonged hypoxia however there follows a further steady increase in basal ventilation and an enhancement of the acute hypoxic response which develops over a period of hours to days. This secondary response is referred to as ventilatory acclimatisation. Acclimatisation is often associated with adaptation to life at altitude but a similar process also occurs in many chronic diseases where hypoxaemia is present.



We know relatively little about the mechanisms of acclimatisation but several lines of evidence indicate that it is largely due to changes in the oxygen sensitivity of peripheral chemoreceptors themselves. There is also evidence that acclimatisation only occurs in response to hypoxia, other chemoreceptor stimuli do not have the same effect. The recent discovery that a hypomorphic mutation in the von Hipple Lindau factor gene has similar effects upon ventilatory control to those of chronic hypoxia, further suggests that hypoxia inducible factor (HIF) signaling may be involved.



The aim of our research therefore is to investigate the hypothesis that acclimatisation involves oxygen dependent control of gene transcription via prolyl hydroxylases and hypoxia inducible factor/s (HIF) which increases the sensitivity and/or number of oxygen sensing type-1 cells in the carotid body. In evaluating this hypothesis we aim to



1) Evaluate the functional significance of HIF signaling in ventilatory acclimatisation by using both gain and loss of function mutations in the HIF signaling pathway. These mutations will be induced acutely in adult mice and their ventilatory responses to both chronic and acute hypoxia will be measured.



2) Investigate the role of prolyl hydroxylases (PHD?s). Since PHD?s control oxygen dependent degradation of HIF we hypothesize that pharmacological inhibition, or induced genetic ablation, of PHD will mimic acclimatisation.



3) Determine the effect of chronic hypoxia and HIF signaling upon carotid body morphology. In particular we seek to establish whether hyperplasia of type-1 cells coincides with the development of acclimatisation.



4) Determine whether chronic hypoxia and HIF signaling alter the intrinsic chemosensitivity of type-1 cells. Specifically we will look at the effects of chronic hypoxia and HIF gain & loss of function mutations on stimulus evoked intracellular calcium signaling events in acutely isolated type-1 cells.

Publications


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Buckler KJ (2015) Functional Properties of Mitochondria in the Type-1 Cell and Their Role in Oxygen Sensing. in Advances in experimental medicine and biology
Holmes AP (2016) Moderate inhibition of mitochondrial function augments carotid body hypoxic sensitivity. in Pflugers Archiv : European journal of physiology