Derivatives of 8-hydroxyquinoline activate angiogenesis by stabilizing functional hypoxia-inducible factor-1α
- Derivatives of 8-hydroxyquinoline activate angiogenesis by stabilizing functional hypoxia-inducible factor-1α
- 양은경; 박현성; 이명진; 김정원
- Issue Date
- 2010 KSBMB
- Hypoxia-inducible factor-1 (HIF-1) as an αβ heterodimer plays an essential role for the regulation of oxygen homeostasis. While both subunits are expressed, only HIF-1α has the oxygen-dependent degradation domain which renders the complex susceptible to the oxygen level. Thus, the levels and activity of HIF-1α are regulated by its post-translational hydroxylation as catalyzed HIF hydroxylases, whose inhibition is attractive from the perspective of developing pharmaceuticals that activate the HIF pathway. Here, we found that 8-hydroxyquinoline derivatives inhibit hydroxylation of proline and asparagine of HIF-1α with varying degrees. In addition to elucidating the inhibitory mechanisms, we assessed their effects in cells that the compounds induce stabilization of HIF-1α and block its ubiquitination, which leads to enhanced transcriptional activation of HIF-1 responsive genes such as vascular endothelial growth factor. Therefore, our results indicate that 8-hydroxyquinoline derivatives possess a pro-angiogenesis potential and thus might have the therapeutic utility in the treatment of ischemic diseases.
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