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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.
Mol Pharmacol. 2007 Jun; 71(6):1676-84.MP

Abstract

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.

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Authors+Show Affiliations

Jeon H
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Korea.
Kim H
No affiliation info available
Choi D
No affiliation info available
Kim D
No affiliation info available
Park SY
No affiliation info available
Kim YJ
No affiliation info available
Kim YM
No affiliation info available
Jung Y
No affiliation info available

MeSH

Cells, CulturedChelating AgentsColonEpithelial CellsHumansHypoxia-Inducible Factor 1Hypoxia-Inducible Factor 1, alpha SubunitProcollagen-Proline DioxygenaseQuercetinUp-RegulationVascular Endothelial Growth Factor A

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17377063

Citation

Jeon, Hyunchu, et al. "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." Molecular Pharmacology, vol. 71, no. 6, 2007, pp. 1676-84.
Jeon H, Kim H, Choi D, et al. 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. Mol Pharmacol. 2007;71(6):1676-84.
Jeon, H., Kim, H., Choi, D., Kim, D., Park, S. Y., Kim, Y. J., Kim, Y. M., & Jung, Y. (2007). 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. Molecular Pharmacology, 71(6), 1676-84.
Jeon H, et al. 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. Mol Pharmacol. 2007;71(6):1676-84. PubMed PMID: 17377063.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Jeon,Hyunchu, AU - Kim,Heejung, AU - Choi,Daekyu, AU - Kim,Duksoo, AU - Park,Shi-Young, AU - Kim,Yung-Jin, AU - Kim,Young Mi, AU - Jung,Yunjin, Y1 - 2007/03/21/ PY - 2007/3/23/pubmed PY - 2007/7/19/medline PY - 2007/3/23/entrez SP - 1676 EP - 84 JF - Molecular pharmacology JO - Mol Pharmacol VL - 71 IS - 6 N2 - 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/17377063/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_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17377063 DB - PRIME DP - Unbound Medicine ER -