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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.

Authors+Show Affiliations

Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -