Induction Of Functional Hypoxia-inducible Factor-1α And Angiogenesis By Derivatives Of 8-hydroxyquinoline

Abstract

Hypoxia-inducible factor-1 (HIF-1) as a complex of α and β subunits mediates a ubiquitous pathway by which mammalian cells sense and respond to hypoxia. In mammalian cells, the levels and activity of HIF-1α are regulated by its post-translational hydroxylation as catalyzed HIF hydroxylases, whose inhibition is thus attractive from the perspective of developing pharmaceuticals that activate the HIF pathway and induce a pro-angiogenic response. We found that 8-hydroxyquinoline and its derivatives inhibit hydroxylation of proline and asparagine of HIF-1α with varying degrees. In addition, they completely block ubiquitination of HIF-1α, which leads to its accumulation and activation of HIF-1-mediated vascular endothelial growth factor transcription and reporter gene activity. Furthermore, in vivo organ models based on the chick chorioallantoic membrane assay demonstrate promotion of new blood vessel formation. Therefore, our results indicate that CQ analogs possess a pro-angiogenesis potential and thus might have the therapeutic utility in the treatment of ischemic diseases.