Fine tuning the HIF-1 'global' O2 sensor for hypobaric hypoxia in Andean high-altitude natives

Included in the acute response of lowlanders exposed to reduced oxygen availability is an elevated red blood cell count due to increased erythropoietin (Epo) synthesis. According to current thinking, hypoxia is "sensed" by hydroxylases that permit Hypoxia Inducible Factor 1alpha (HIF-1alpha) to complex with HIF-1beta to form a transcriptional activator (HIF-1) that drives expression of hypoxia-sensitive genes (such as EPO) under hypoxic conditions. In altitude-adapted Andean natives, the Epo hypoxic response may be blunted; however, our data indicate that the DNA sequences of the genes encoding Epo (including the 3' regulatory region) and HIF-1alpha appear to be conserved. Hence, adaptive changes in the Andean hypoxic response are not a consequence of changes in the primary sequence of these proteins or of known transcriptional regulatory domains of EPO. These results suggest that the altered erthropoietic response in Andean natives reflects adaptations in hypoxia sensing, rather than hypoxia response, mechanisms.