Abstract
Many of the biological effects of a low partial pressure of oxygen in the atmosphere have been recognized and studied for many years. For example Viault in 1890 found an increase in red cell concentration in the blood at altitude following the prediction by Paul Bert that this would occur. Thirty-five years later the Heymans father and son duo discovered the role of the peripheral chemoreceptors in stimulating ventilation in response to hypoxemia. Then some 20 years further on von Euler and Liljestrand described the response of the pulmonary circulation to alveolar hypoxia leading to the recognition of high altitude pulmonary hypertension. Most current textbooks for medical students limit their discussion of the physiological effects of high altitude hypoxia to polycythemia, hyperventilation and pulmonary hypertension with perhaps a nod towards the increased concentration of capillaries in skeletal muscle and changes of oxidative enzymes inside cells.
So pity the medical school lecturers, the textbook authors, and particularly the medical and graduate students when Semenza and colleagues described Hypoxia Inducible Factors (HIFs). This discovery has caused a revolution in high altitude biology. HIFs are transcription factors that respond to hypoxia and control the flow, that is transcription, of genetic information from DNA to messenger RNA. This is done by helping or hindering RNA polymerase binding to DNA. The result is either increasing the rate of gene transcription, that is upregulation, or decreasing the rate of gene transcription, or downregulation. It is now believed that in cellular hypoxia, the transcription of several hundred mRNAs is increased, and the expression of an equal number of mRNAs is decreased. Thus the biological responses to hypoxia are legion.
Most oxygen-breathing species express these transcriptional factors indicating that HIFs have been highly conserved. In fact HIF-1 is expressed in very primitive animals such as the worm Caenorhabditis elegans that lacks specialized respiratory or circulatory systems. This suggests that HIF was initially developed to allow individual cells to survive in low-oxygen environments.
There is now evidence that Hypoxia Inducible Factors control genes that have multiple functions right across the physiological spectrum. Among those affected are mitochondrial genes involved with energy utilization, glycolytic enzyme genes influencing anaerobic metabolism, genes associated with Vascular Endothelial Growth Factor controlling angiogenesis, genes related to nitric oxide metabolism that apparently inhibit calcium ion channels causing pulmonary vasodilatation, erythropoietin genes affecting red blood cell production, and genes controlling the induction of tyrosine hydroxylase that affect carotid body chemosensors. Hypoxia Inducible Factors therefore constitute a master switch in the general response of the body to hypoxia.
Two or three special conditions might be mentioned. As indicated above, the fact that HIFs are expressed in very primitive animals suggests that their initial function may have been to allow individual cells to survive in low-oxygen environments. Consistent with this, HIF-1 assists cell survival under hypoxic conditions by switching metabolism from oxidative to glycolytic. Is this a clue to the Lactate Paradox which remains poorly understood?
Another fascinating area is the link between HIF and hypoxic pulmonary hypertension. It is known that increases in intracellular calcium ion concentration and intracellular pH contribute to the growth and contraction of pulmonary artery smooth muscle cells under hypoxic conditions. There is some evidence that both of these factors are mediated by HIF-1. It now turns out that digoxin, a drug that has been used to treat heart failure or dropsy for over 200 years inhibits HIF-1. Perhaps this will be useful some day in the treatment of hypoxic pulmonary hypertension.
Finally there is interesting new work on HIF and intermittent hypoxia which is common at high altitude because of periodic breathing. Surprisingly it has been shown that in rats, intermittent hypoxia upregulates HIF-1 α but downregulates HIF-2 α. Studies show that the downregulation of HIF-2 α in rats exposed to intermittent hypoxia can be inhibited by calpain proteases, and this may have implications for preventing the pathology resulting from intermittent hypoxia.
The discovery of Hypoxia Inducible Factors has enormous implications for high altitude medicine and biology. In the next issue of this Journal a special feature is planned to look at some of these new consequences of oxygen sensing.