PMID- 17377063
OWN - NLM
STAT- MEDLINE
DCOM- 20070718
LR  - 20131121
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 71
IP  - 6
DP  - 2007 Jun
TI  - 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.
PG  - 1676-84
AB  - 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.
FAU - Jeon, Hyunchu
AU  - Jeon H
AD  - Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National 
      University, Busan, Korea.
FAU - Kim, Heejung
AU  - Kim H
FAU - Choi, Daekyu
AU  - Choi D
FAU - Kim, Duksoo
AU  - Kim D
FAU - Park, Shi-Young
AU  - Park SY
FAU - Kim, Yung-Jin
AU  - Kim YJ
FAU - Kim, Young Mi
AU  - Kim YM
FAU - Jung, Yunjin
AU  - Jung Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070321
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Chelating Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 9IKM0I5T1E (Quercetin)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
SB  - IM
MH  - Cells, Cultured
MH  - Chelating Agents/metabolism
MH  - Colon/cytology
MH  - Epithelial Cells/*drug effects/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*physiology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
MH  - Procollagen-Proline Dioxygenase/*antagonists & inhibitors/metabolism
MH  - Quercetin/*pharmacology
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/biosynthesis/drug effects/*metabolism
EDAT- 2007/03/23 09:00
MHDA- 2007/07/19 09:00
CRDT- 2007/03/23 09:00
PHST- 2007/03/23 09:00 [pubmed]
PHST- 2007/07/19 09:00 [medline]
PHST- 2007/03/23 09:00 [entrez]
AID - mol.107.034041 [pii]
AID - 10.1124/mol.107.034041 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2007 Jun;71(6):1676-84. doi: 10.1124/mol.107.034041. Epub 2007 Mar 
      21.