Laboratory of Biomedicinal/Medicinal Chemistry, College of Pharmacy, Pusan National University, Pusan, Republic of Korea.
J Nutr Biochem. 2010 Sep;21(9):809-17. doi: 10.1016/j.jnutbio.2009.06.002. Epub 2009 Sep 8.
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-1alpha protein in cells, which occurred by inhibition of HIF prolyl hydroxylase (HPH), the key enzyme for von Hippel-Lindau-dependent HIF-1alpha degradation. CAPE inhibition of HPH and induction of HIF-1alpha 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.
咖啡酸苯乙酯（CAPE）是来自蜜蜂的蜂胶的一种活性成分。我们研究了 CAPE 介导的对缺血/再灌注（I/R）损伤的保护作用的潜在分子机制，并分析了导致 CAPE 效应的结构。CAPE 诱导缺氧诱导因子-1（HIF-1）α蛋白，同时反式激活 HIF-1 靶基因血管内皮生长因子和血红素加氧酶-1，在 I/R 损伤中发挥保护作用。CAPE 通过抑制 HIF 脯氨酰羟化酶（HPH）延迟了细胞中 HIF-1α蛋白的降解，HPH 是 von Hippel-Lindau 依赖性 HIF-1α降解的关键酶。CAPE 对 HPH 的抑制作用和 HIF-1α蛋白的诱导作用被铁的高剂量中和。儿茶酚部分是一种螯合基团，对于 HPH 抑制是必需的，而迈克尔反应受体中的双键（-C=C-）的氢化则显著降低了效力。CAPE 中苯乙基部分的去除（用甲基部分取代）严重恶化了其对 HPH 的抑制活性。我们的数据表明，CAPE 对 I/R 损伤的有益作用可能归因于通过抑制 HPH 激活 HIF-1 途径，并揭示了 CAPE 的螯合部分作为药效团，而双键和苯乙基部分有助于抑制 HPH。
