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

Abstract

We investigated a molecular mechanism underlying quercetinmediated 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␣ protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1␣ hydroxylation and subsequent von Hippel Lindau-dependent HIF-1␣ degradation. HPH inhibition by quercetin was neutralized significantly by an elevated dose of iron. Consistent with this, cellular induction of HIF-1␣ 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 3Ј and 4Ј of the B ring, enabled the flavonoid to inhibit HPH and subsequently induce HIF-1␣. 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.

Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells

“…Quercetin is known to chelate Fe 2þ (Leopoldini et al, 2006) and it has been suggested that the increase in HIF-1a is a direct result of this property (Jeon et al, 2007;Park et al, 2007;Triantafyllou et al, 2007). Fe 2þ is a cofactor for HPH, an enzyme which catalyses the hydroxylation of HIF-1a thus targeting it ultimately for degradation via the proteosome.…”

Effect of pioglitazone, quercetin, and hydroxy citric acid on vascular endothelial growth factor messenger RNA (VEGF mRNA) expression in experimentally induced nonalcoholic steatohepatitis (NASH)

“…Quercetin, which is a flavonol found in several varieties of berries at concentrations of up to 70-80 mg/kg dry wt., has been found to inhibit the growth and stimulate the apoptosis of cancer cells (14).…”

Modulation of hypoxia-inducible factors (HIF) from an integrative pharmacological perspective

“…In fact, quercetin inhibits HIF-1a protein synthesis under hypoxia in the human prostate cancer cell line LNCaP, colon cancer cell line CX-1, and breast cancer cell line SkBr3 [49]. However, under normoxia increases HIF-1a in the human colon epithelial cell lines HCT116 and SW620 [50], as well as HIF-1a/HIF-2a by impairing its degradation by PHDs in the human prostate adenocarcinoma cell lines LNCaP, DU-145 and PC-3 or HCT116 cells [50,51]. Genistein, another flavonoid and inhibitor of tyrosine kinases, completely blocks the synthesis of both HIF-1 subunits in human retinal pigment epithelium cells [52] as well as HIF-1 DNA-binding activity [53].…”