Hypoxia and human disease—and the Journal of Molecular Medicine

Abstract

This special issue of the Journal of Molecular Medicine is focused on the role of hypoxia in the pathogenesis of human disease. Oxygen homeostasis is a critical organizing principle of metazoan evolution, development, and physiology. The seven invited reviews in this issue highlight the rapid progress that is being made in delineating the molecular mechanisms that result in disruption of oxygen homeostasis in different disease states, the extent to which this disruption contributes to disease pathogenesis, and the prospects for novel therapies that target pathways involved in adaptive (or maladaptive) responses to hypoxia. In their review, entitled “Hypoxia and Gastrointestinal Disease,” Cormac Taylor and Sean Colgan summarize the results of published studies analyzing hypoxia-induced gene expression in intestinal epithelial cells and the role of hypoxia in the pathogenesis of inflammatory bowel disease. In “Hypoxia and Cancer,” Christiane Brahimi-Horn, Johanna Chiche, and Jacques Pouyssegur discuss the causes and consequences of intratumoral hypoxia. Joseph Garcia discusses ischemic heart disease with a specific focus on alterations in cardiac metabolism that promote the survival of ischemic cells. In “Hypoxia and Chronic Lung Disease,” Rubin Tuder and colleagues review the role of hypoxia in respiratory distress syndrome, high altitude pulmonary edema, pulmonary arterial hypertension, and chronic obstructive pulmonary disease. It is remarkable that despite receiving oxygen from the bronchial circulation and directly from the alveolar air sacs, hypoxia can develop within the lungs (even at sea level) and contribute to pathogenic tissue remodeling. Masaomi Nangaku and Kai-Uwe Eckardt discuss the role of the kidney in oxygen homeostasis, particularly in the production of erythropoietin, which is the glycoprotein hormone that controls red blood cell production. They also summarize recent data indicating that chronic hypoxia in the tubulointerstitium represents a final common pathway to end-stage kidney disease. Rajiv Ratan and his colleagues discuss novel strategies for promoting hypoxic adaptation in neurons as a means to prevent or treat brain injury after stroke. These strategies are based on recent advances in our understanding of the molecular physiology of oxygen sensing. Annelies Zinkernagel, Randall Johnson, and Victor Nizet review data indicating that the same transcriptional regulatory system that promotes adaptive responses to hypoxia, which are described in the other six papers in this issue, is also required for neutrophil inflammatory and innate immune functions. They also review data indicating that obligate intracellular bacteria and oncogenic viruses modulate hypoxia response pathways in host cells. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays an important role in cellular and systemic responses to reduced oxygen availability in all metazoan species. Purification of HIF-1 from human cells revealed that it is heterodimer composed of HIF-1α and HIF-1β subunits, which dimerize and bind to DNA containing the core sequence 5′-(A/G)CGTG-3′. Database searches for proteins that were homologous to HIF-1α led to the identification of HIF-2α, which can also dimerize with HIF-1β and bind to an overlapping but distinct set of target genes. HIF-1α and HIF-2α are each negatively regulated by O2-dependent hydroxylation of key proline and asparagine residues that dramatically reduce protein half-life and transcriptional activity, respectively, under aerobic conditions. Although I admit my bias in focusing on the role of J Mol Med (2007) 85:1293–1294 DOI 10.1007/s00109-007-0285-z