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First published on March 21, 2007; DOI: 10.1124/mol.107.034041

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Received for publication January 9, 2007.
Revised March 20, 2007.
Accepted for publication March 21, 2007.

Quercetin activates an angiogenic pathway HIF-1-VEGF by inhibiting HIF-prolyl hydroxylase: A structural analysis of quercetin for inhibiting HIF-prolyl hydroxylase

Hyunchu Jeon 1, Heejung Kim 1, Daekyu Choi 1, Duksoo Kim 1, Shi-Young Park 1, Yung-Jin Kim 1, Young Mi Kim 1, Yunjin Jung 1*

1 Pusan National University

* Address correspondence to: E-mail: jungy{at}pusan.ac.kr

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-1{alpha} protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1{alpha} hydroxylation and subsequent VHL-dependent HIF-1{alpha} degradation. HPH inhibition by quercetin was neutralized significantly by elevated dose of iron. Consistent with this, cellular induction of HIF-1{alpha} 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 position 3' and 4' of the B ring, enabled the flavonoid to inhibit HPH and subsequently induce HIF-1{alpha} 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.


Key words: Structure/function/mechanism, Metals and chelators, Angiogenesis


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