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
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
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DOI：
10.1124/mol.107.034041
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发表时间：
2007-06-01
影响因子：
3.6
通讯作者：
Jung, Yunjin
中科院分区：
文献类型：
--
作者：
Jeon, Hyunchu;Kim, Heejung;Jung, Yunjin
我们研究了槲皮素介导的改善结肠粘膜损伤的分子机制，并分析了有助于槲皮素作用的化学结构。槲皮素不仅在结肠上皮细胞系中而且在发炎的结肠组织中上调血管内皮生长因子（VEGF），这是一种溃疡愈合因子。源自槲皮素处理的结肠上皮细胞的 VEGF 促进管形成。 VEGF 诱导依赖于槲皮素介导的缺氧诱导因子 1 (HIF-1) 激活。槲皮素延迟 HIF-1 α 蛋白消失，这是通过抑制 HIF-脯氨酰羟化酶 (HPH) 来实现的，HPH 是 HIF-1 α 羟化和随后 von Hippel Lindau 依赖性 HIF-1 α 降解的关键酶。槲皮素对 HPH 的抑制作用可通过增加铁剂量而显着中和。与此一致的是，通过铁预处理消除了槲皮素对 HIF-1 α 的细胞诱导作用。槲皮素中的两个铁螯合部分，即 C 环 3 位的 -OH 和/或 B 环 3' 和 4' 位的 -OH，使类黄酮能够抑制 HPH 并随后诱导 HIF-1 α。我们的数据表明，槲皮素的临床效果可能部分归因于通过抑制HPH激活血管生成途径HIF-1-VEGF，并且槲皮素的螯合部分是抑制HPH所必需的。
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 von Hippel Lindau-dependent HIF-1 alpha degradation. HPH inhibition by quercetin was neutralized significantly by an 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 positions 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.