Hypoxia‐ inducible factor 1 α

Hypoxia inducible factor-1 (HIF-1) is a master regulator under conditions of decreased oxygen availability. The HIF-1 transcriptional system senses decreased oxygen availability and transmits this signal into patho-physiological responses such as angiogenesis, erythropoiesis, vasomotor control, an altered energy metabolism, as well as cell survival decisions. Among recent advances are the discoveries that reactive nitrogen species, oxygen species, cytokines, and growth factors participate in stability regulation of HIF-1alpha and HIF-1 transactivation during normoxia. NO, as a signaling molecule makes HIF-1alpha an attractive target under conditions of NO formation that may be attributed to both, physiology and pathology. Although initial observations showed that NO inhibits hypoxia-induced HIF-1alpha stabilization and HIF-1 transcriptional activation, later studies indicated that exposure of various cells to chemically diverse NO donors or conditions of endogenous NO formation under normoxic conditions induced HIF-1alpha accumulation, HIF-1-DNA binding, and activation of downstream target gene expression. Besides hypoxia, nitric oxide (NO) and/or NO-derived species regulate HIF-1α abundance and activity. Recent studies indicate that under normoxic conditions, chemically diverse NO donors, enhanced NO formation from inducible NO-synthase, or NO formation in a coculture system induced HIF-1α stabilization and transcriptional activation of HIF-1 target gene expression. Both increased protein synthesis due to NO-induced phosphatidylinositol 3-kinase or mitogen-activated protein kinase signaling and decreased degradation of HIF-1α by NO-dependent inhibition of PHD1, -2, and -3 activity have been reported to contribute to this effect. However, under hypoxic conditions, NO appears to have an opposite role in regulating HIF-1α, because several NO donors were found to decrease HIF-1α stabilization and HIF-1 transcriptional activation. It was reported that mitochondria play a role in NO regulation of HIF expression under hypoxia. Mitochondrial oxygen consumption was reduced by NO inhibition of the cytochrome c oxidase. This would leave more oxygen for O2-dependent HIF prolyl hydroxylases (PHDs; modify HIF-1α, which is sent to proteasomal degradation under normoxia). Alternatively, the inhibitory effect of NO on hypoxia-induced HIF-1α was explained by increased NO-derived species and/or reactive oxygen species that contribute to destabilization of HIF-1α by reactivation of PHD activity. In addition, calcium and calpain- family of calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes) expressed ubiquitously in mammals and many other tissues- were found to contribute to the degradation of HIF-1α by NO under hypoxia. Interestingly, NO increased the activity of PHDs that were inhibited by hypoxia-mimicking agents like CoCl2 or desferrioxamine.