Quercetin activates an angiogenic pathway, hypoxia inducible factor (HIF)-1-vascular endothelial growth factor, by inhibiting HIF-prolyl hydroxylase: a structural analysis of quercetin for inhibiting HIF-prolyl hydroxylase.
We investigated a molecular mechanism underlying quercetin-mediated amelioration of colonic mucosal injury and analyzed chemical structure contributing to the quercetin's effect. Quercetin up-regulated vascular endothelial growth factor (VEGF), an ulcer healing factor, not only in colon epithelial cell lines but also in the inflamed colonic tissue. VEGF derived from quercetin-treated colon epithelial cells promoted tube formation. The VEGF induction was dependent on quercetin-mediated hypoxia-inducible factor-1 (HIF-1) activation. Quercetin delayed HIF-1alpha protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1alpha hydroxylation and subsequent von Hippel Lindau-dependent HIF-1alpha degradation. HPH inhibition by quercetin was neutralized significantly by an elevated dose of iron. Consistent with this, cellular induction of HIF-1alpha by quercetin was abolished by pretreatment with iron. Two iron-chelating moieties in quercetin, -OH at position 3 of the C ring and/or -OH at positions 3' and 4' of the B ring, enabled the flavonoid to inhibit HPH and subsequently induce HIF-1alpha. Our data suggest that the clinical effect of quercetin may be partly attributed to the activation of an angiogenic pathway HIF-1-VEGF via inhibiting HPH and the chelating moieties of quercetin were required for inhibiting HPH.
Jeon
Hyunchu
H
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Korea.
Kim
Heejung
H
Choi
Daekyu
D
Kim
Duksoo
D
Park
Shi-Young
SY
Kim
Yung-Jin
YJ
Kim
Young Mi
YM
Jung
Yunjin
Y
D002478:Cells, Cultured; D002614:Chelating Agents / Q000378:metabolism; D003106:Colon / Q000166:cytology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*
D002614:Chelating Agents; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D011794:Quercetin; D011393:Procollagen-Proline Dioxygenase