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-1α protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1α hydroxylation and subsequent von Hippel Lindau-dependent HIF-1α degradation. HPH inhibition by quercetin was neutralized significantly by an elevated dose of iron. Consistent with this, cellular induction of HIF-1α 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-1α. 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.
Footnotes
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This work was supported by grant KRF-2005-003-E00324 (2005) from the Korea Research Foundation and grant R01-2006-000-10521-0 (2006) from the Basic Research Program of the Korea Science and Engineering Foundation.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.034041.
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ABBREVIATIONS: IBD, inflammatory bowel disease; HIF-1, hypoxia inducible factor-1; NFκB, nuclear factor-κB; HPH, hypoxia inducible factor-proly hydroxylase; VEGF, vascular endothelial growth factor; TNBS, 2,4,6-trinotrobenzene-sulfonic acid; VHL, von Hippel Lindau; ARNT, aryl hydrocarbon receptor nuclear translocator; PMSF, phenylmethylsulfonyl fluoride; HA, hemagglutinin; PAGE, polyacrylamide gel electrophoresis; IVT, in vitro-translated; ELISA, enzyme-linked immunosorbent assay; MG-132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received January 8, 2007.
- Accepted March 21, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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