The dietary flavonoid quercetin modulates HIF-1 alpha activity in endothelial cells

The mechanism of activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) has been studied extensively. Under normal cellular oxygen conditions protein levels of the alpha subunit (HIF-1 alpha) are kept low due to massive ubiquitination and subsequent proteosomal degradation. However, during hypoxia ubiquitination is inhibited, causing stabilisation of the HIF-1 alpha protein. HIF-1 alpha can then translocate to the nucleus and facilitate transcription of numerous target genes, the majority of which are involved in glycolysis and angiogenesis via heterodimerisation with the beta subunit (HIF-1 beta/ARNT). Until now hypoxia has been the only naturally occurring signal shown to activate this transcription factor. We report here that the dietary flavonoid quercetin also activates HIF-1 alpha in all steps of its activation pathway, in a manner similar to hypoxia. We found that quercetin, an inhibitor of Ser/Thr kinases, stabilises HIF-1 alpha and causes nuclear localisation of the protein in a transcriptionally active state. Taken together these results strongly indicate that the dietary flavonoid quercetin regulates HIF-1 function at normal oxygen concentrations.