Hypoxia-inducible factor-1α under the control of nitric oxide

Decreased oxygen availability evokes adaptive responses, which are primarily under the gene regulatory control of hypoxia-inducible factor 1 (HIF-1). HIF-1 is a heterodirner composed of the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) protein HIF-1alpha (alpha) and the aryl hydrocarbon nuclear translocator (ARNT), also known as HIF-1beta (beta). The HIF-1 transcriptional system senses decreased oxygen availability and transmits this signal into pathophysiological responses, such as angiogenesis, erythropoiesis, vasomotor control, an altered energy metabolism, and/or ceil survival decisions. It is now appreciated that nitric oxide (NO) and/or derived reactive nitrogen species (RNS) participate in stability control of HIF-1 alpha. Although initial observations showed that NO inhibits hypoxia-incluced HIF-1a stabilization and HIF-1 transcriptional activation, later studies revealed that the exposure of cells from different species to chemically diverse NO donors, or conditions of endogenous NO formation, induced HIF-1 alpha accumulation, HIF-1-DNA binding, and activation of downstream target gene expression under normoxic conditions. The opposing effects of NO under hypoxia versus normoxia are discussed based on direct and indirect reaction properties of NO, taking metal interactions as well as secondary reaction products, generated in the presence of oxygen or superoxide, into account. Considering HIF-1 alpha as a target that is controlled by the bioavailability of NO helps in the understanding of how signaling mechanisms are attributed to physiological and pathological transmission of NO actions with broad implications for medicine.