Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication
Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication
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DOI：
10.1016/j.jnutbio.2009.06.002
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发表时间：
2010-09-01
影响因子：
5.6
通讯作者：
Jung, Yunjin
中科院分区：
文献类型：
--
作者：
Choi, Daekyu;Han, Jeongoh;Jung, Yunjin
咖啡酸苯乙酯(CAPE)是蜜蜂蜂胶中的活性成分。我们研究了CAPE介导的抗I/R损伤的潜在分子机制，并分析了CAPE效应诱导的缺氧诱导因子-1(HIF-1)α蛋白的结构，同时反式激活了在I/R损伤中起保护作用的HIF-1靶基因血管内皮生长因子和血红素加氧酶-1。CAPE延缓了细胞内HIF-1α蛋白的降解，这是通过抑制HIF-1α依赖的HIF-1α降解的关键酶--HPH来实现的。CAPE对HPH的抑制和对HIF-1α蛋白的诱导可被更高剂量的铁中和。邻苯二酚是HPH抑制所必需的螯合基团，而Michael反应受体上的双键(-C=C-)的氢化显著降低了CAPE的苯乙基部分(以甲基取代)的去除效力，严重恶化了其对HPH的抑制活性。结果提示，CAPE对缺血再灌注损伤的保护作用可能归因于通过抑制HPH激活HIF-1通路，并揭示CAPE的螯合部分起药效作用，而双键和苯乙基部分有助于抑制HPH。(C)2010 Elsevier Inc.保留所有权利。
Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee We investigated a potential molecular mechanism underlying a CAPE-mediated protective effect against ischemia/reperfusion (I/R) Injury and analyzed the structure contributing to the CAPE effect CAPE induced hypoxia-inducible factor-1 (HIF-1) alpha protein, concomitantly transactivating the HIF-1 target genes vascular endothelial growth factor and heme oxygenase-1, which play a protective role in I/R injury. CAPE delayed the degradation of HIF-1 alpha protein in cells, which occurred by inhibition of HIF prolyl hydroxylase (HPH), the key enzyme for von Hippel-Lindau-dependent HIF-1 alpha degradation. CAPE inhibition of HPH and induction of HIF-1 alpha protein were neutralized by an elevated dose of Iron. The catechol moiety, a chelating group, is essential for HPH inhibition, while hydrogenation of the double bond (-C=C-) in the Michael reaction acceptor markedly reduced potency Removal of the phenethyl moiety of CAPE (substitution with the methyl moiety) severely deteriorated its inhibitory activity for HPH. Our data suggest that a beneficial effect of CAPE on I/R injury may be ascribed to the activation of HIF-1 pathway via inhibition of HPH and reveal that the chelating moiety of CAPE acted as a pharmacophore while the double bond and phenethyl moiety assisted in inhibiting HPH. (C) 2010 Elsevier Inc. All rights reserved.