Oxygen Sensing, Homeostasis, and Disease

Hypoxia plays critical roles in the pathobiology of heart disease, cancer, stroke, and chronic lung disease, which are responsible for 60% of deaths in the United States. This review summarizes advances in our un derstanding of how cells sense and respond to changes in oxygen availability and the physiologic or pathologic consequences of these responses in the context of chronic diseases. The role of hypoxia in inflammatory disorders was recently reviewed in the Journal 1 and is therefore not discussed here. M e ch a nis m s of Signa l T r a nsduc t ion i n H y p ox i a Humans have evolved complex circulatory, respiratory, and neuroendocrine systems to ensure that oxygen levels are precisely maintained, since an excess or deficiency may result in the death of cells, tissue, or the organism. As discussed below, oxygen homeostasis represents an organizing principle for understanding evolution, devel opment, physiology, and disease. Historically, oxygen sensing was thought to be limited to specialized cells, such as the glomus cells of the carotid body, which depo larize within milliseconds in response to hypoxemia by means of incompletely understood mechanisms. 2 We now recognize that all nucleated cells in the body sense and respond to hypoxia. Under conditions of reduced oxygen availability, hypoxia-inducible factor 1 (HIF-1) regulates the expression of genes that mediate adaptive responses. 3-6 In hypoxic cells, the transcription of several hundred messenger RNAs (mRNAs) is increased, and the expression of an equal number of mRNAs is decreased. The changes are dependent on HIF-1 in both cases, but HIF-1 binding is detected only at genes with increased expression. HIF-1 decreases mRNA expression indirectly by regulating transcriptional repressors and microRNAs. 3-6 HIF-1 was first identified in human cells as a regulator of erythropoietin, the hor