INSIGHT FROM POPULATIONS DWELLING AT HIGH ALTITUDE
Hypoxia can also serve as a model for certain adaptations that create resilience to disease but this can only be studied by an experiment of nature. For example, studying high-lander populations has revealed a number of genes that allow for adaptation to chronic hypoxia [47]. These groups, such an Andean’s, Ethiopians, and Tibetans have evolved variations in their erythrocyte homeostasis, angiogenesis, vaso-regulation, cell death, immune response, cognition, and various other processes that are often implicated in disease. The aforementioned populations had adapted a lower expression of the gene EDNRB, which has a large regulatory region of single-nucleotide polymorphisms and transcription binding sites [48]. Mice with this gene knocked out showed extreme hypoxia tolerance [49]. Congruently, patients with ischemic heart disease show significantly higher levels of EDNRB and antagonists of this gene are used to reduce induced high-altitude pulmonary artery pressure [50, 51]. All of this evidence supports this highlander adaptation as a valuable model for cardiac disease. Such studies have also identified key epigenetic shifts that require further mechanism investigation. Despite the promising translational model of highlanders, studying these groups has its limitations; they are difficult to access and have been isolated for long enough to have accrued hypoxia-unrelated and thus confounding genetic differences. This emphasizes the need to categorize variations in hypoxia related adaptations amongst the general population as well as investigate how easily inducible these epigenetic changes are for possible therapeutic intervention.