Hypoxia and high altitude. The molecular response.

Increased erythropoietin plasma levels and the consequent augmented production of red blood cells is the best known systemic adaptation to reduced oxygen partial pressure (pO2). Intensive research during the last years revealed that the molecular mechanism behind the regulation of erythropoietin is ubiquitous and has far more implications than first thought. Erythropoietin regulation results from the activation of the hypoxia-inducible factor-1 (HIF-1) pathway under hypoxic conditions. HIF-1 is a heterodimer consisting of an oxygen sensitive--HIF-1--and an oxygen-independent subunit--HIF-1beta (also known as the aryl hydrocarbon receptor nuclear translocator--ARNT). In addition to erythropoietin, more than 30 genes are now known to be up-regulated by HIF-1. Recently, the critical involvement of HIF-1alpha post-translational modifications in the cellular oxygen sensing mechanism was discovered. In this review we will focus on the regulation of the HIF-1 pathway and the cellular oxygen sensor and discuss their implications in high altitude hypoxia.